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Wang X, Chen W, Liu S, Xu Y, Xiong Z, Li Y, Huang L, Jiang L, Zhang J, Sun L, Zhang Y, Liu M. Detection of mitophagy in live cells with indole derived near-infrared fluorogenic probes. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 340:126368. [PMID: 40367757 DOI: 10.1016/j.saa.2025.126368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2025] [Revised: 04/29/2025] [Accepted: 05/08/2025] [Indexed: 05/16/2025]
Abstract
Mitophagy is an indispensable cellular process that plays a crucial role in regulating mitochondrial quality control and cellular metabolism. Therefore, monitoring the changes in the mitochondrial and lysosomal microenvironment during the mitophagy process is extremely important. However, existing mitophagy probes only target changes in a single indicator (viscosity, pH value, or polarity) within the microenvironment, which may reduce the selectivity and accuracy of assessing mitophagy in complex biological settings. To address this, we have developed a dual-channel detection near-infrared (NIR) fluorescent probe (ADMI). In vitro analysis experiments have shown that ADMI not only responds to pH and activates the NIR fluorescence channel but also that the green fluorescence channel exhibits high sensitivity to changes in polarity. This dual-response mechanism probe enables dual fluorescent detection of pH and polarity, providing a highly promising tool for monitoring the microenvironment of mitophagy in living cells. Ultimately, we applied ADMI to real-time monitoring of mitophagy induced by starvation or rapamycin, during which the decrease in pH and polarity resulted in a red shift in wavelength and increased fluorescence. Additionally, ADMI was able to observe changes in mitochondria during ferroptosis. This probe may serve as a useful tool for imaging mitophagy in living cells.
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Affiliation(s)
- Xuanyuan Wang
- College of Chemistry and Material Science, Hengyang Normal University, Hengyang 421001, PR China
| | - Wen Chen
- College of Chemistry and Material Science, Hengyang Normal University, Hengyang 421001, PR China.
| | - Shuangling Liu
- State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082 Hunan, PR China
| | - Yihong Xu
- College of Chemistry and Material Science, Hengyang Normal University, Hengyang 421001, PR China
| | - Zhimei Xiong
- College of Chemistry and Material Science, Hengyang Normal University, Hengyang 421001, PR China
| | - Yingzi Li
- College of Chemistry and Material Science, Hengyang Normal University, Hengyang 421001, PR China
| | - Leyuan Huang
- College of Chemistry and Material Science, Hengyang Normal University, Hengyang 421001, PR China
| | - Lu Jiang
- College of Chemistry and Material Science, Hengyang Normal University, Hengyang 421001, PR China
| | - Jingting Zhang
- College of Chemistry and Material Science, Hengyang Normal University, Hengyang 421001, PR China
| | - Leying Sun
- College of Chemistry and Material Science, Hengyang Normal University, Hengyang 421001, PR China
| | - Yuan Zhang
- College of Chemistry and Material Science, Hengyang Normal University, Hengyang 421001, PR China.
| | - Mengqin Liu
- College of Chemistry and Material Science, Hengyang Normal University, Hengyang 421001, PR China
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2
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Xu S, Jia J, Mao R, Cao X, Xu Y. Mitophagy in acute central nervous system injuries: regulatory mechanisms and therapeutic potentials. Neural Regen Res 2025; 20:2437-2453. [PMID: 39248161 PMCID: PMC11801284 DOI: 10.4103/nrr.nrr-d-24-00432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 06/11/2024] [Accepted: 07/22/2024] [Indexed: 09/10/2024] Open
Abstract
Acute central nervous system injuries, including ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, traumatic brain injury, and spinal cord injury, are a major global health challenge. Identifying optimal therapies and improving the long-term neurological functions of patients with acute central nervous system injuries are urgent priorities. Mitochondria are susceptible to damage after acute central nervous system injury, and this leads to the release of toxic levels of reactive oxygen species, which induce cell death. Mitophagy, a selective form of autophagy, is crucial in eliminating redundant or damaged mitochondria during these events. Recent evidence has highlighted the significant role of mitophagy in acute central nervous system injuries. In this review, we provide a comprehensive overview of the process, classification, and related mechanisms of mitophagy. We also highlight the recent developments in research into the role of mitophagy in various acute central nervous system injuries and drug therapies that regulate mitophagy. In the final section of this review, we emphasize the potential for treating these disorders by focusing on mitophagy and suggest future research paths in this area.
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Affiliation(s)
- Siyi Xu
- Department of Neurology, Nanjing Drum Tower Hospital, Clinical College of Jiangsu University, Nanjing, Jiangsu Province, China
| | - Junqiu Jia
- Department of Neurology, Nanjing Drum Tower Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, Jiangsu Province, China
| | - Rui Mao
- Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
| | - Xiang Cao
- Department of Neurology, Nanjing Drum Tower Hospital, Clinical College of Jiangsu University, Nanjing, Jiangsu Province, China
- Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
- State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, Jiangsu Province, China
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, China
- Nanjing Neurology Medical Center, Nanjing, Jiangsu Province, China
| | - Yun Xu
- Department of Neurology, Nanjing Drum Tower Hospital, Clinical College of Jiangsu University, Nanjing, Jiangsu Province, China
- Department of Neurology, Nanjing Drum Tower Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, Jiangsu Province, China
- Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
- State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, Jiangsu Province, China
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, China
- Nanjing Neurology Medical Center, Nanjing, Jiangsu Province, China
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3
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Palabiyik AA. The role of Bcl‑2 in controlling the transition between autophagy and apoptosis (Review). Mol Med Rep 2025; 32:172. [PMID: 40242969 PMCID: PMC12045647 DOI: 10.3892/mmr.2025.13537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 04/01/2025] [Indexed: 04/18/2025] Open
Abstract
The Bcl‑2 protein family serves a key role in maintaining cellular homeostasis by regulating the balance between autophagy and apoptosis. The present review aimed to summarize interactions of Bcl‑2 with key proteins, including Beclin 1, Bax and Bcl‑2 homologous antagonist/killer, as well as its influence on cellular processes such as mitophagy, nutrient sensing and endoplasmic reticulum stress response. The impact of post‑translational modifications of Bcl‑2, including phosphorylation, ubiquitination and sumoylation, is discussed with respect to their regulatory roles under stress. In pathological states, Bcl‑2 upregulation in cancer suppresses apoptosis and autophagy, thereby facilitating tumor survival and resistance to chemotherapy. Conversely, in neurodegenerative diseases, impaired autophagy and increased apoptosis contribute to neuronal loss. Therapeutic strategies targeting Bcl‑2 (for example inhibitors such as venetoclax, navitoclax, obatoclax and combination therapies involving autophagy modulators) were evaluated for their potential efficacy. There is lack of understanding of tissue‑specific functions of Bcl‑2 and its interactions with non‑coding RNAs. Future research should prioritize these areas and leverage advanced single‑cell technologies to elucidate the real‑time dynamics of Bcl‑2 in cell processes. The present review highlights the key role of Bcl‑2 in cell fate determination and highlights its potential as a therapeutic target, offering insight for the development of innovative treatments for cancer, neurodegenerative disorder and age‑related diseases.
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Affiliation(s)
- Ahmet Alperen Palabiyik
- Department of Nursing, Faculty of Health Sciences, Ardahan University, Çamlıçatak, Ardahan 75002, Turkey
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4
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Chen Y, Deng H, Zhang N. Autophagy-targeting modulation to promote peripheral nerve regeneration. Neural Regen Res 2025; 20:1864-1882. [PMID: 39254547 PMCID: PMC11691477 DOI: 10.4103/nrr.nrr-d-23-01948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 02/22/2024] [Accepted: 03/29/2024] [Indexed: 09/11/2024] Open
Abstract
Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms. Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration. However, recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration, particularly in the context of traumatic injuries. Consequently, autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration. Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths, thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation. These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration. A range of autophagy-inducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries. This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration, summarizing the potential drugs and interventions that can be harnessed to promote this process. We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.
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Affiliation(s)
- Yan Chen
- Department of Obstetrics and Gynecology, West China Second Hospital, Sichuan University, Chengdu, Sichuan Province, China
- Key Laboratory of Birth Defects and Women and Children’s Diseases, Ministry of Education, Sichuan University, Chengdu, Sichuan Province, China
- Laboratory of Reproductive Endocrinology and Reproductive Regulation, Sichuan University, Chengdu, Sichuan Province, China
| | - Hongxia Deng
- Key Laboratory of Birth Defects and Women and Children’s Diseases, Ministry of Education, Sichuan University, Chengdu, Sichuan Province, China
- Laboratory of Reproductive Endocrinology and Reproductive Regulation, Sichuan University, Chengdu, Sichuan Province, China
| | - Nannan Zhang
- Key Laboratory of Birth Defects and Women and Children’s Diseases, Ministry of Education, Sichuan University, Chengdu, Sichuan Province, China
- National Center for Birth Defect Monitoring, West China Second University Hospital, Sichuan University, Chengdu, Sichuan Province, China
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Dong H, Lyu Y, Huang CY, Tsai SY. Limiting cap-dependent translation increases 20S proteasomal degradation and protects the proteomic integrity in autophagy-deficient skeletal muscle. Autophagy 2025; 21:1212-1227. [PMID: 39878121 PMCID: PMC12087647 DOI: 10.1080/15548627.2025.2457925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 01/21/2025] [Accepted: 01/21/2025] [Indexed: 01/31/2025] Open
Abstract
Postmitotic skeletal muscle critically depends on tightly regulated protein degradation to maintain proteomic stability. Impaired macroautophagy/autophagy-lysosomal or ubiquitin-proteasomal protein degradation causes the accumulation of damaged proteins, ultimately accelerating muscle dysfunction with age. While in vitro studies have demonstrated the complementary nature of these systems, their interplay at the organism levels remains poorly understood. Here, our study reveals novel insights into this complex relationship in autophagy-deficient skeletal muscle. We demonstrated that despite a compensatory increase in proteasome level in response to autophagy impairment, 26S proteasome activity was not proportionally enhanced in autophagy-deficient skeletal muscle. This functional deficit was partly attributed to reduced ATP levels to fuel the 26S proteasome. Remarkably, we found that activation of EIF4EBP1, a crucial inhibitor of cap-dependent translation, restored and even augmented proteasomal function through dual mechanisms. First, genetically activating EIF4EBP1 enhanced both ATP-dependent 26S proteasome and ATP-independent 20S proteasome activities, thereby expanding overall protein degradation capacity. Second, EIF4EBP1 activation caused muscle fiber transformation and increased mitochondrial biogenesis, thus replenishing ATP levels for 26S proteasome activation. Notably, the improved performance of the 20S proteasome in EIF4EBP1-activated skeletal muscle was attributed to an increased abundance of the immunoproteasome, a subtype specially adapted to function under oxidative stress conditions. This dual action of EIF4EBP1 activation preserved proteomic integrity in autophagy-deficient skeletal muscle. Our findings uncover a novel role of EIF4EBP1 in improving protein quality control, presenting a promising therapeutic strategy for autophagy-related muscular disorders and potentially other conditions characterized by proteostatic imbalance.Abbreviations: 3-MA: 3-methyladenine; ACAC/ACC: acetyl-Coenzyme A carboxylase; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; ATG7: autophagy related 7; ATP: adenosine triphosphate; ATP5F1A/ATP5A: ATP synthase F1 subunit alpha; CKM-Cre: creatine kinase, muscle-Cre; CMA: chaperone-mediated autophagy; CTSB: cathepsin B; CTSK: cathepsin K; CTSL: cathepsin L; CUL3: cullin 3; EDL: extensor digitorum longus; EIF4E: eukaryotic translation initiation factor 4E; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; EIF4F: eukaryotic translation initiation factor 4F complex; FBXO32/ATROGIN1/MAFbx: F-box protein 32; GFP: green fluorescent protein; IFNG/IFN-γ: interferon gamma; KEAP1: kelch-like ECH-associated protein 1; LAMP1: lysosomal-associated membrane protein 1; LAMP2: lysosomal-associated membrane protein 2; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; Myl1/Mlc1f-Cre: myosin, light polypeptide 1 (promoter driving Cre recombinase); mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NFE2L1/NRF1: nuclear factor, erythroid derived 2, like 1; NFE2L2/NRF2: nuclear factor, erythroid derived 2, like 2; NFKB1/NFκB1: nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105; OXPHOS: oxidative phosphorylation; PPARGC1A/PGC1α: peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; PSMB5: proteasome (prosome, macropain) subunit, beta type 5; PSMB6: proteasome (prosome, macropain) subunit, beta type 6; PSMB7: proteasome (prosome, macropain) subunit, beta type 7; PSMB8: proteasome (prosome, macropain) subunit, beta type 8 (large multifunctional peptidase 7); PSMB9: proteasome (prosome, macropain) subunit, beta type 9 (large multifunctional peptidase 2); PSMB10: proteasome (prosome, macropain) subunit, beta type 10; PSME1: proteasome (prosome, macropain) activator subunit 1 (PA28 alpha); PSME2: proteasome (prosome, macropain) activator subunit 2 (PA28 beta); RBX1: ring-box 1; SQSTM1/p62: sequestosome 1; SREBF1/SREBP1: sterol regulatory element binding transcription factor 1; STAT3: signal transducer and activator of transcription 3; TRIM63/MURF1: tripartite motif-containing 63; ULK1: unc-51 like kinase 1; UPS: ubiquitin-proteasome system.
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Affiliation(s)
- Han Dong
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yifan Lyu
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Chien-Yung Huang
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Shih-Yin Tsai
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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6
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Zhang J, Wang H, Xue X, Wu X, Li W, Lv Z, Su Y, Zhang M, Zhao K, Zhang X, Jia C, Zhu F. Human endogenous retrovirus W family envelope protein (ERVWE1) regulates macroautophagy activation and micromitophagy inhibition via NOXA1 in schizophrenia. Virol Sin 2025:S1995-820X(25)00065-3. [PMID: 40419114 DOI: 10.1016/j.virs.2025.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 05/22/2025] [Indexed: 05/28/2025] Open
Abstract
The human endogenous retrovirus type W envelope glycoprotein (ERVWE1), located at chromosome 7q21-22, has been implicated in the pathophysiology of schizophrenia. Our previous studies have shown elevated ERVWE1 expression in schizophrenia patients. Growing evidence suggests that autophagy dysfunction contributes to schizophrenia, yet the relationship between ERVWE1 and autophagy remains unclear. In this study, bioinformatics analysis of the human prefrontal cortex RNA microarray dataset (GSE53987) revealed that differentially expressed genes were predominantly enriched in autophagy-related pathways. Clinical data further demonstrated that serum levels of microtubule-associated protein 1 light chain 3β (LC3B), a key marker of macroautophagy, were significantly elevated in schizophrenia patients compared to controls, and positively correlated with ERVWE1 expression. Cellular and molecular experiments suggested that ERVWE1 promoted macroautophagy by increasing the LC3B II/I ratio, enhancing autophagosome formation, and reducing sequestosome 1 (SQSTM1) expression via upregulation of NADPH oxidase activator 1 (NOXA1). Concurrently, NOXA1 downregulated the expression of key micromitophagy-related genes, including PTEN-induced kinase 1 (PINK1), Parkin RBR E3 ubiquitin-protein ligase (Parkin), and the pyruvate dehydrogenase E1 subunit α 1 (PDHA1). As a result, ERVWE1, via NOXA1, inhibited micromitophagy by suppressing the expression of PINK1, Parkin, and PDHA1, thereby leading to impaired production of mitochondrial-derived vesicles (MDVs). Mechanistically, ERVWE1 enhanced NOXA1 transcription by upregulating upstream transcription factor 2 (USF2). In conclusion, ERVWE1 promotes macroautophagy and inhibits micromitophagy through USF2-NOXA1 axis, providing novel mechanistic insight into the role autophagy dysregulation in schizophrenia. These findings suggest that targeting autophagy pathways may offer novel therapeutic strategies for schizophrenia treatment.
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Affiliation(s)
- Jiahang Zhang
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Huiling Wang
- Department of Psychiatry, Renmin Hospital of Wuhan University, Jiefang Road No.238, Wuhan, 430060, China
| | - Xing Xue
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Xiulin Wu
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Wenshi Li
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhao Lv
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yaru Su
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Mengqi Zhang
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Kexin Zhao
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Xu Zhang
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Chen Jia
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China; Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China.
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7
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Tai L, Zhu D, Tang P, Li J, Li J, Li P, Tao Z, Lei H, Miao K, Wang HX, Lin S, Zhang L, Dou M, Han Y, Shen HM, Deng C, Wang L, Di LJ. Reciprocal stabilization of CtBP and TRIM28 represses autophagy to promote metastasis. Nat Struct Mol Biol 2025:10.1038/s41594-025-01554-0. [PMID: 40374929 DOI: 10.1038/s41594-025-01554-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 04/05/2025] [Indexed: 05/18/2025]
Abstract
Deciphering the processes through which cancer cells overcome stress, escape a repressive microenvironment and metastasize remains a challenge. Autophagy has been demonstrated to regulate cancer metastasis and C-terminal binding protein (CtBP) has been previously implicated in promoting metastasis in breast cancer. Here we identify the formation of a complex between CtBP and tripartite-motif-containing protein 28 (TRIM28) in the nucleus. Interestingly, this complex regulates the stability of both proteins, as the removal of either partner leads to degradation of the other. Furthermore, the stability of this complex in the nucleus inhibits autophagy through two independent mechanisms. Firstly, the formation of the complex sequesters TRIM28 in the nucleus, preventing its involvement in and its degradation through autophagy. Secondly, this complex participates in the suppression of PTEN expression and leads to inhibition of Unc-51-like kinase 1-mediated autophagy through activation of the protein kinase B-mammalian target of rapamycin pathway. Using mammary gland-specific CtBP-knockout mice, we demonstrate that repression of autophagy by the CtBP-TRIM28 complex modulates luminal duct formation. In breast cancer models, CtBP-TRIM28-dependent inhibition of cellular autophagy also promotes malignant metastasis. Therefore, our study reveals similarities between the mechanisms driving tumor progression and those involved in normal mammary gland development, potentially helping to pave the way toward targeted intervention in breast cancer metastasis.
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Affiliation(s)
- Lixin Tai
- Department of Biological Sciences, Faculty of Health Sciences, University of Macau, Macau, China
- Ministry of Education Frontiers Science Center for Precision Oncology (FSCPO), University of Macau, Macau, China
| | - Dongliang Zhu
- Department of Biological Sciences, Faculty of Health Sciences, University of Macau, Macau, China
- Ministry of Education Frontiers Science Center for Precision Oncology (FSCPO), University of Macau, Macau, China
| | - Ping Tang
- Department of Biological Sciences, Faculty of Health Sciences, University of Macau, Macau, China
- Ministry of Education Frontiers Science Center for Precision Oncology (FSCPO), University of Macau, Macau, China
| | - Jiajia Li
- Department of Biological Sciences, Faculty of Health Sciences, University of Macau, Macau, China
- Ministry of Education Frontiers Science Center for Precision Oncology (FSCPO), University of Macau, Macau, China
| | - Junyi Li
- Department of Biological Sciences, Faculty of Health Sciences, University of Macau, Macau, China
- Ministry of Education Frontiers Science Center for Precision Oncology (FSCPO), University of Macau, Macau, China
| | - Peipei Li
- Department of Biological Sciences, Faculty of Health Sciences, University of Macau, Macau, China
- Ministry of Education Frontiers Science Center for Precision Oncology (FSCPO), University of Macau, Macau, China
| | - Zhonghua Tao
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Haipeng Lei
- Department of Biological Sciences, Faculty of Health Sciences, University of Macau, Macau, China
- Ministry of Education Frontiers Science Center for Precision Oncology (FSCPO), University of Macau, Macau, China
| | - Kai Miao
- Department of Biological Sciences, Faculty of Health Sciences, University of Macau, Macau, China
- Ministry of Education Frontiers Science Center for Precision Oncology (FSCPO), University of Macau, Macau, China
| | - Hong-Xia Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shuhai Lin
- State Key Laboratory of Cellular Stress Biology, School of Life Science, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Lei Zhang
- Department of Pathology, Basic Medical Science College, Harbin Medical University, Harbin, China
| | - Man Dou
- Department of Biological Sciences, Faculty of Health Sciences, University of Macau, Macau, China
- Metabolomics core, Faculty of Health Sciences, University of Macau, Macau, China
| | - Yu Han
- Department of Biological Sciences, Faculty of Health Sciences, University of Macau, Macau, China
- Genomics, Bioinformatics and Single Cell Analysis Core, Faculty of Health Sciences, University of Macau, Macau, China
| | - Han-Ming Shen
- Department of Biological Sciences, Faculty of Health Sciences, University of Macau, Macau, China
- Ministry of Education Frontiers Science Center for Precision Oncology (FSCPO), University of Macau, Macau, China
| | - Chuxia Deng
- Department of Biological Sciences, Faculty of Health Sciences, University of Macau, Macau, China
- Ministry of Education Frontiers Science Center for Precision Oncology (FSCPO), University of Macau, Macau, China
| | - Li Wang
- Department of Biological Sciences, Faculty of Health Sciences, University of Macau, Macau, China
- Ministry of Education Frontiers Science Center for Precision Oncology (FSCPO), University of Macau, Macau, China
- Metabolomics core, Faculty of Health Sciences, University of Macau, Macau, China
| | - Li-Jun Di
- Department of Biological Sciences, Faculty of Health Sciences, University of Macau, Macau, China.
- Ministry of Education Frontiers Science Center for Precision Oncology (FSCPO), University of Macau, Macau, China.
- Department of Pathology, Basic Medical Science College, Harbin Medical University, Harbin, China.
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8
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Zhuang Y, Zhang X, Zhang S, Sun Y, Wang H, Chen Y, Zhang H, Zou P, Feng Y, Lu X, Chen P, Xu Y, Li JZ, Gao H, Jin L, Kong X. Chaperone-mediated autophagy manipulates PGC1α stability and governs energy metabolism under thermal stress. Nat Commun 2025; 16:4455. [PMID: 40360527 PMCID: PMC12075589 DOI: 10.1038/s41467-025-59618-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 04/29/2025] [Indexed: 05/15/2025] Open
Abstract
Thermogenic proteins are down-regulated under thermal stress, including PGC1α· However, the molecular mechanisms are not fully understood. Here, we addressed that chaperone-mediated autophagy could regulate the stability of PGC1α under thermal stress. In mice, knockdown of Lamp2a, one of the two components of CMA, in BAT showed increased PGC1α protein and improved metabolic phenotypes. Combining the proteomics of brown adipose tissue (BAT), structure prediction, co-immunoprecipitation- mass spectrum and biochemical assays, we found that PARK7, a Parkinson's disease causative protein, could sense the temperature changes and interact with LAMP2A and HSC70, respectively, subsequently manipulate the activity of CMA. Knockout of Park7 specific in BAT promoted BAT whitening, leading to impaired insulin sensitivity and energy expenditure at thermoneutrality. Moreover, inhibiting the activity of CMA by knockdown of LAMP2A reversed the effects induced by Park7 ablation. These findings suggest CMA is required for BAT to sustain thermoneutrality-induced whitening through degradation of PGC1α.
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Affiliation(s)
- Yixiao Zhuang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Xinyi Zhang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Shuang Zhang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Yunpeng Sun
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China
| | - Hui Wang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Yuxuan Chen
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Hanyin Zhang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Penglai Zou
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Yonghao Feng
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Xiaodan Lu
- Precisional Medical Center, Jilin Province People's Hospital, Changchun, 130021, China
| | - Peijie Chen
- School of Exercise and Health, Shanghai University of Sport, Shanghai, 200438, China
| | - Yi Xu
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200438, China
| | - John Zhong Li
- Department of Molecular Biology and Biochemistry, Nanjing Medical University, Nanjing, Jiangsu, 211166, China
- Jiangsu Key Laboratory of Molecular Targets and Intervention of Metabolic Disease, Nanjing Medical University, Nanjing, Jiangsu, 211166, China
- Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, 211166, China
| | - Huanqing Gao
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China.
| | - Li Jin
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China.
| | - Xingxing Kong
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China.
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200438, China.
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, 200438, China.
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9
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Li J, Liu T, Xian M, Wei J. Therapeutic applications of exercise in neurodegenerative diseases: focusing on the mechanism of SIRT1. Mol Cell Biochem 2025:10.1007/s11010-025-05299-8. [PMID: 40358811 DOI: 10.1007/s11010-025-05299-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 04/27/2025] [Indexed: 05/15/2025]
Abstract
Neurodegenerative diseases comprise a group of central nervous system disorders marked by progressive neuronal degeneration and dysfunction. Their pathogenesis is multifactorial, involving oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. Recent research has highlighted the potential of exercise as a non-pharmacological intervention for both the prevention and treatment of these disorders. In particular, exercise has received growing attention for its capacity to upregulate the expression and activity of SIRT1, a critical mediator of neuroprotection via downstream signaling pathways. SIRT1, a key member of the Sirtuin family, is a nicotinamide adenine dinucleotide (NAD +)-dependent class III histone deacetylase. It plays an essential role in regulating cellular metabolism, energy homeostasis, gene expression, and cellular longevity. In the context of neurodegenerative diseases, SIRT1 confers neuroprotection by modulating multiple signaling cascades through deacetylation, suppressing neuronal apoptosis, and promoting neural repair and regeneration. Exercise enhances SIRT1 expression and activity by increasing NAD + synthesis and utilization, improving intracellular redox balance, alleviating oxidative stress-induced inhibition of SIRT1, and thereby promoting its activation. Moreover, exercise may indirectly modulate SIRT1 function by influencing interacting molecular networks. This review summarizes recent advances in the therapeutic application of exercise for neurodegenerative diseases, with a focus on SIRT1 as a central mechanism. It examines how exercise mediates neuroprotection through the regulation of SIRT1 and its associated molecular mechanisms and signaling pathways. Finally, the paper discusses the potential applications and challenges of integrating exercise and SIRT1-targeted strategies in the management of neurodegenerative diseases, offering novel perspectives for the development of innovative treatments and improvements in patients' quality of life.
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Affiliation(s)
- Jingwen Li
- Institute for Sports and Brain Health, School of Physical Education, Henan University, Kaifeng, 475004, Henan, China
- Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng, 475004, China
| | - Tingting Liu
- Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng, 475004, China
| | - Meiyan Xian
- Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng, 475004, China
| | - Jianshe Wei
- Institute for Sports and Brain Health, School of Physical Education, Henan University, Kaifeng, 475004, Henan, China.
- Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng, 475004, China.
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10
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Zhang Z, Tan R, Xiong Z, Feng Y, Chen L. Dysregulation of autophagy during photoaging reduce oxidative stress and inflammatory damage caused by UV. Front Pharmacol 2025; 16:1562845. [PMID: 40421222 PMCID: PMC12104874 DOI: 10.3389/fphar.2025.1562845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 04/21/2025] [Indexed: 05/28/2025] Open
Abstract
Photoaging, the premature aging of skin due to chronic ultraviolet (UV) exposure, is a growing concern in dermatology and cosmetic science. While UV radiation is known to induce DNA damage, oxidative stress, and inflammation in skin cells, recent research unveils a promising countermeasure: autophagy. This review explores the intricate relationship between autophagy and photoaging, highlighting how this cellular recycling process can mitigate UV-induced damage. We begin by examining the differential impacts of UVA and UVB radiation on skin cells and the role of oxidative stress in accelerating photoaging. Next, we delve into the molecular mechanisms of autophagy, including its various forms and regulatory pathways. Central to this review is the discussion of autophagy's protective functions, such as the clearance of damaged organelles and proteins, and its role in maintaining genomic integrity. Furthermore, we address the current challenges in harnessing autophagy for therapeutic purposes, including the need for selective autophagy inducers and a deeper understanding of its context-dependent effects. By synthesizing recent advancements and proposing future research directions, this review underscores the potential of autophagy modulation as a novel strategy to prevent and treat photoaging. This comprehensive analysis aims to inspire further investigation into autophagy-based interventions, offering new hope for preserving skin health in the face of environmental stressors.
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Affiliation(s)
- Zhongsong Zhang
- School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China
| | - Run Tan
- Department of Dermatology, Chengdu Second People‘s Hospital, Chengdu, Sichuan Province, China
- School of Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Zuanyu Xiong
- Department of Medical Aesthetics, Nanbu People‘s Hospital, Nanchong, China
| | - Yanyan Feng
- Department of Dermatology, Chengdu Second People‘s Hospital, Chengdu, Sichuan Province, China
- School of Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Long Chen
- School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China
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11
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Zhang R, Vooijs MA, Keulers TG. Key Mechanisms in Lysosome Stability, Degradation and Repair. Mol Cell Biol 2025; 45:212-224. [PMID: 40340648 DOI: 10.1080/10985549.2025.2494762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 04/10/2025] [Accepted: 04/10/2025] [Indexed: 05/10/2025] Open
Abstract
Lysosomes are organelles that play pivotal roles in macromolecule digestion, signal transduction, autophagy, and cellular homeostasis. Lysosome instability, including the inhibition of lysosomal intracellular activity and the leakage of their contents, is associated with various pathologies, including cancer, neurodegenerative diseases, inflammatory diseases and infections. These lysosomal-related pathologies highlight the significance of factors contributing to lysosomal dysfunction. The vulnerability of the lysosomal membrane and its components to internal and external stimuli make lysosomes particularly susceptible to damage. Cells are equipped with mechanisms to repair or degrade damaged lysosomes to prevent cell death. Understanding the factors influencing lysosome stabilization and damage repair is essential for developing effective therapeutic interventions for diseases. This review explores the factors affecting lysosome acidification, membrane integrity, and functional homeostasis and examines the underlying mechanisms of lysosomal damage repair. In addition, we summarize how various risk factors impact lysosomal activity and cell fate.
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Affiliation(s)
- Rui Zhang
- Department of Radiation Oncology (MAASTRO)/GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Marc A Vooijs
- Department of Radiation Oncology (MAASTRO)/GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Tom Gh Keulers
- Department of Radiation Oncology (MAASTRO)/GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, The Netherlands
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12
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Attanasio S. Autophagy in cancer and protein conformational disorders. FEBS Lett 2025. [PMID: 40342093 DOI: 10.1002/1873-3468.70061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 04/09/2025] [Accepted: 04/11/2025] [Indexed: 05/11/2025]
Abstract
Autophagy is a catabolic process by which cells maintain cellular homeostasis through the degradation of dysfunctional cytoplasmic components, such as toxic misfolded proteins and damaged organelles, within the lysosome. It is a multistep process that is tightly regulated by nutrient, energy, and stress-sensing mechanisms. Autophagy plays a pivotal role in various biological processes, including protein and organelle quality control, defense against pathogen infections, cell metabolism, and immune surveillance. As a result, autophagy dysfunction is linked to a variety of pathological conditions. The role of autophagy in cancer is complex and dynamic. Depending on the context, autophagy can have both tumor-suppressive and pro-tumorigenic effects. In contrast, its role is more clearly defined in protein conformational disorders, where autophagy serves as a mechanism to reduce toxic protein aggregation, thereby improving cellular homeostasis. Because autophagy-based therapies hold promising potential for the treatment of cancer and protein conformational disorders, this review will highlight the latest findings and advancements in these areas.
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Affiliation(s)
- Sergio Attanasio
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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13
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Minuti A, Raffaele I, Scuruchi M, Lui M, Muscarà C, Calabrò M. Role and Functions of Irisin: A Perspective on Recent Developments and Neurodegenerative Diseases. Antioxidants (Basel) 2025; 14:554. [PMID: 40427436 DOI: 10.3390/antiox14050554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2025] [Revised: 04/28/2025] [Accepted: 05/05/2025] [Indexed: 05/29/2025] Open
Abstract
Irisin is a peptide derived from fibronectin type III domain-containing protein 5 (FNDC5) and is primarily produced by muscle fibers under the regulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) during exercise. Irisin has been the subject of extensive research due to its potential as a metabolic regulator and its antioxidant properties. Notably, it has been associated with protective actions within the brain. Despite growing interest, many questions remain regarding the molecular mechanisms underlying its effects. This review summarizes recent findings on irisin, highlighting its pleiotropic functions and the biological processes and molecular cascades involved in its action, with a particular focus on the central nervous system. Irisin plays a crucial role in neuron survival, differentiation, growth, and development, while also promoting mitochondrial homeostasis, regulating apoptosis, and facilitating autophagy-processes essential for normal neuronal function. Emerging evidence suggests that irisin may improve conditions associated with non-communicable neurological diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and multiple sclerosis. Given its diverse benefits, irisin holds promise as a novel therapeutic agent for preventing and treating neurological diseases.
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Affiliation(s)
- Aurelio Minuti
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy
| | - Ivana Raffaele
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy
| | - Michele Scuruchi
- Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy
| | - Maria Lui
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy
| | - Claudia Muscarà
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy
| | - Marco Calabrò
- IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy
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14
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Barmaki H, Nourazarian A, Yousefi H, Khalilnezhad A, Shahriyari E, Khaki-Khatibi F. Dual Mechanism of Docosahexaenoic acid (DHA) in Alzheimer's Disease: PAD4 Inhibition and Autophagy Stimulation. Mol Neurobiol 2025:10.1007/s12035-025-05008-y. [PMID: 40316879 DOI: 10.1007/s12035-025-05008-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Accepted: 04/29/2025] [Indexed: 05/04/2025]
Abstract
Alzheimer's disease (AD), which affects millions globally, is marked by progressive cognitive decline and neurodegeneration driven by protein aggregation and chronic inflammation. Emerging evidence has implicated peptidyl arginine deiminase 4 (PAD4) activity and impaired autophagy as key contributors to disease progression. In this study, we explored the neuroprotective potential of DHA in an in vitro model of AD. DHA was administered before arachidonic acid (AA), a proinflammatory agent that mimics AD-like cellular stress. DHA treatment reduced PAD4 expression, enhanced autophagy-related gene expression, and attenuated inflammatory and oxidative stress markers. It also lowered amyloid-beta accumulation and preserved neuronal integrity. These outcomes suggest a potential dual mechanism by which DHA may influence Alzheimer's-related pathology via PAD4 inhibition and autophagy stimulation in vitro. While these findings offer important mechanistic insights, further validation in animal models and clinical contexts is essential before therapeutic relevance can be confirmed.
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Affiliation(s)
- Haleh Barmaki
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Nourazarian
- Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran
| | - Hadi Yousefi
- Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran
| | - Asghar Khalilnezhad
- Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Elham Shahriyari
- Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Fatemeh Khaki-Khatibi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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15
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Ye K, Zhao X, Liu L, Ge F, Zheng F, Liu Z, Tian M, Han X, Gao X, Xia Q, Wang D. Comparative Analysis of Human Brain RNA-seq Reveals the Combined Effects of Ferroptosis and Autophagy on Alzheimer's Disease in Multiple Brain Regions. Mol Neurobiol 2025; 62:6128-6149. [PMID: 39710824 DOI: 10.1007/s12035-024-04642-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 11/22/2024] [Indexed: 12/24/2024]
Abstract
Ferroptosis and autophagy are closely associated with Alzheimer's disease (AD). Elevated ferric ion levels can induce oxidative stress and chronic inflammatory responses, resulting in brain tissue damage and further neurological cell damage. Autophagy in Alzheimer's has a dual role. On one hand, it protects neurons by removing β-amyloid and cellular damage products caused by oxidative stress and inflammation. On the other hand, abnormal autophagy is linked to neuronal apoptosis and neurodegeneration. However, the intricate interplay between ferroptosis and autophagy in AD remains insufficiently explored. This study focuses on the roles of ferroptosis and autophagy in AD and their interconnection through bioinformatics analysis, shedding light on the disease. Ferroptosis and autophagy significantly correlate with the development and course of AD. Using PPI network analysis and unsupervised consistency clustering analysis, we uncovered a complex network of interactions between ferroptosis and autophagy during disease progression, demonstrating a significant congruence in their modification patterns. Functional analyses further demonstrated that ferroptosis and autophagy together affect the immunological status and synaptic regulation in hippocampal regions in patients with AD, which significantly impacts the start and progression of the disease.
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Affiliation(s)
- Ke Ye
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China
| | - Xue Zhao
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China
| | - Lulu Liu
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China
| | - Fangliang Ge
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China
| | - Feifei Zheng
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China
| | - Zijie Liu
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China
| | - Mengjie Tian
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China
| | - Xinyu Han
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China
| | - Xu Gao
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China.
- Key Laboratory of Heilongjiang Province for Genetically Modified Animals, Harbin Medical University, Harbin, 150000, Heilongjiang, China.
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, 150000, Heilongjiang, China.
| | - Qing Xia
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China.
| | - Dayong Wang
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China.
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16
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Fu Y, Zhang J, Qin R, Ren Y, Zhou T, Han B, Liu B. Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases. Pharmacol Rev 2025; 77:100053. [PMID: 40187044 DOI: 10.1016/j.pharmr.2025.100053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 12/05/2024] [Indexed: 04/07/2025] Open
Abstract
Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due to their intricate pathogenesis and substantial variability among patients, including differences in environmental exposures and genetic predispositions. One of the defining characteristics of NDs is widely reported to be the buildup of misfolded proteins. For example, Alzheimer disease is marked by amyloid beta and hyperphosphorylated Tau aggregates, whereas Parkinson disease exhibits α-synuclein aggregates. Amyotrophic lateral sclerosis and frontotemporal dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, and fused-in sarcoma protein aggregates, and Huntington disease involves mutant huntingtin and polyglutamine aggregates. These misfolded proteins are the key biomarkers of NDs and also serve as potential therapeutic targets, as they can be addressed through autophagy, a process that removes excess cellular inclusions to maintain homeostasis. Various forms of autophagy, including macroautophagy, chaperone-mediated autophagy, and microautophagy, hold a promise in eliminating toxic proteins implicated in NDs. In this review, we focus on elucidating the regulatory connections between autophagy and toxic proteins in NDs, summarizing the cause of the aggregates, exploring their impact on autophagy mechanisms, and discussing how autophagy can regulate toxic protein aggregation. Moreover, we underscore the activation of autophagy as a potential therapeutic strategy across different NDs and small molecules capable of activating autophagy pathways, such as rapamycin targeting the mTOR pathway to clear α-synuclein and Sertraline targeting the AMPK/mTOR/RPS6KB1 pathway to clear Tau, to further illustrate their potential in NDs' therapeutic intervention. Together, these findings would provide new insights into current research trends and propose small-molecule drugs targeting autophagy as promising potential strategies for the future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview of the potential of activating autophagy to eliminate toxic protein aggregates in the treatment of neurodegenerative diseases. It also elucidates the fascinating interrelationships between toxic proteins and the process of autophagy of "chasing and escaping" phenomenon. Moreover, the review further discusses the progress utilizing small molecules to activate autophagy to improve the efficacy of therapies for neurodegenerative diseases by removing toxic protein aggregates.
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Affiliation(s)
- Yuqi Fu
- Institute of Precision Drug Innovation and Cancer Center, the Second Hospital of Dalian Medical University, Dalian, China; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jin Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; School of Pharmaceutical Sciences of Medical School, Shenzhen University, Shenzhen, China
| | - Rui Qin
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yueting Ren
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Brain Science, Faculty of Medicine, Imperial College, London, UK
| | - Tingting Zhou
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai, China.
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Bo Liu
- Institute of Precision Drug Innovation and Cancer Center, the Second Hospital of Dalian Medical University, Dalian, China; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
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17
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Hao B, Lin S, Liu H, Xu J, Chen L, Zheng T, Zhang W, Dang Y, Reiter RJ, Li C, Zhai H, Xia Q, Fan L. Baicalein tethers CD274/PD-L1 for autophagic degradation to boost antitumor immunity. Autophagy 2025; 21:917-933. [PMID: 39710370 PMCID: PMC12013432 DOI: 10.1080/15548627.2024.2439657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 12/02/2024] [Accepted: 12/04/2024] [Indexed: 12/24/2024] Open
Abstract
Immune checkpoint inhibitors, especially those targeting CD274/PD-L1yield powerful clinical therapeutic efficacy. Thoughmuch progress has been made in the development of antibody-basedCD274 drugs, chemical compounds applied for CD274degradation remain largely unavailable. Herein,baicalein, a monomer of traditional Chinese medicine, isscreened and validated to target CD274 and induces itsmacroautophagic/autophagic degradation. Moreover, we demonstrate thatCD274 directly interacts with MAP1LC3B (microtubule associatedprotein 1 light chain 3 beta). Intriguingly, baicalein potentiatesCD274-LC3 interaction to facilitate autophagic-lysosomal degradationof CD274. Importantly, targeted CD274. degradation via baicaleininhibits tumor development by boosting T-cell-mediated antitumorimmunity. Thus, we elucidate a critical role of autophagy-lysosomalpathway in mediating CD274 degradation, and conceptually demonstratethat the design of a molecular "glue" that tethers the CD274-LC3interaction is an appealing strategy to develop CD274 inhibitors incancer therapy.Abbreviations: ATTECs: autophagy-tethering compounds; AUTACs: AUtophagy-TArgeting Chimeras; AUTOTACs: AUTOphagy-TArgeting Chimeras; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; BiFC: bimolecular fluorescence complementation; BafA1: bafilomycin A1; CD274/PD-L1/B7-H1: CD274 molecule; CQ: chloroquine; CGAS: cyclic GMP-AMP synthase; DAPI: 4'6-diamino-2-phenylindole; FITC: fluorescein isothiocyanate isomer; GFP: green fluorescent protein; GZMB: granzyme B; IHC: immunohistochemistry; ICB: immune checkpoint blockade; KO: knockout; KD: equilibrium dissociation constant; LYTAC: LYsosome-TArgeting Chimera; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MST: microscale thermophoresis; NFAT: nuclear factor of activated T cells; NFKB/NF-kB: nuclear factor kappa B; NSCLC: non-small-cell lung cancer; PDCD1: programmed cell death 1; PROTACs: PROteolysis TArgeting Chimeras; PRF1: perforin 1; PE: phosphatidylethanolamine; PHA: phytohemagglutinin; PMA: phorbol 12-myristate 13-acetate; STAT: signal transducer and activator of transcription; SPR: surface plasmon resonance; TILs: tumor-infiltrating lymphocyte; TME: tumor microenvironment.
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Affiliation(s)
- Bingjie Hao
- Institute of Energy Metabolism and Health, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shumeng Lin
- Institute of Energy Metabolism and Health, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Haipeng Liu
- Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Junfang Xu
- Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Li Chen
- Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Tiansheng Zheng
- Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wen Zhang
- Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yifang Dang
- Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Russel J. Reiter
- Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Chaoqun Li
- Institute of Energy Metabolism and Health, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hong Zhai
- Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qing Xia
- Institute of Energy Metabolism and Health, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lihong Fan
- Institute of Energy Metabolism and Health, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Respiratory Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
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18
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Wang Y, Luo S, Sun H, Huang S, Shan L, Zhang J. Covalent inhibitors possessing autophagy-modulating capabilities: charting novel avenues in drug design and discovery. Drug Discov Today 2025; 30:104347. [PMID: 40180310 DOI: 10.1016/j.drudis.2025.104347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 03/11/2025] [Accepted: 03/25/2025] [Indexed: 04/05/2025]
Abstract
Autophagy is a crucial cellular process in degrading damaged organelles and maintaining cellular homeostasis. By forming irreversible bonds with specific proteins, covalent inhibitors present a distinct advantage in regulating autophagy and its related pathways. These inhibitors can provide sustained modulation of autophagy at lower doses, improving therapeutic efficacy while minimizing adverse effects. We discuss their mechanisms, including how they affect autophagy-related enzymes and pathways, and their potential applications in the treatment of cancers and other autophagy-related disorders. Studying autophagy-related pathway targets will provide new insights for the development of covalent inhibitors and enhance therapeutic strategies for complex conditions.
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Affiliation(s)
- Yutong Wang
- Department of Neurology, Laboratory of Neuro-system and Multimorbidity, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China
| | - Shiyu Luo
- Chengdu Shishi High School, Chengdu 610041 Sichuan, China
| | - Hongbao Sun
- Department of Neurology, Laboratory of Neuro-system and Multimorbidity, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China
| | - Shuai Huang
- School of Life Science and Engineering Southwest Jiaotong University, Chengdu 610031 Sichuan, China.
| | - Lianhai Shan
- School of Life Science and Engineering Southwest Jiaotong University, Chengdu 610031 Sichuan, China.
| | - Jifa Zhang
- Department of Neurology, Laboratory of Neuro-system and Multimorbidity, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041 Sichuan, China.
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19
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Bowman B. Distribution and dynamics of hyphal organelles. Fungal Genet Biol 2025; 178:103982. [PMID: 40154940 DOI: 10.1016/j.fgb.2025.103982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/12/2025] [Accepted: 03/18/2025] [Indexed: 04/01/2025]
Abstract
Filamentous fungi have been very useful organisms for the investigation of organelles in eukaryotic cells. The structure and function of fungal organelles is generally very similar to that observed in animal cells. However, the nature of a "cell" in many filamentous fungi is unusual, because in many of these organisms the filaments are structured as a large syncytium. In the Ascomycota hyphae are typically a very long tube divided into different compartments by an incomplete cell wall called the septum. The pore in the middle of the septum is large enough to allow virtually all organelles to move from one hyphal compartment to another. In this review, I will look at the dynamics of this movement of organelles and describe what we know about how the structure and distribution of organelles varies from one hyphal compartment to another.
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Affiliation(s)
- Barry Bowman
- Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA, United States..
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20
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Ling LA, Boukhalfa A, Kung AH, Yang VK, Chen HH. Advances in Targeted Autophagy Modulation Strategies to Treat Cancer and Associated Treatment-Induced Cardiotoxicity. Pharmaceuticals (Basel) 2025; 18:671. [PMID: 40430490 DOI: 10.3390/ph18050671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/24/2025] [Accepted: 04/28/2025] [Indexed: 05/29/2025] Open
Abstract
Autophagy, an evolutionarily conserved process, plays an important role in cellular homeostasis and human diseases. Cardiovascular dysfunction, which presents during cancer treatment or in cancer-free individuals years after treatment, is a growing clinical challenge. Millions of cancer survivors and patients face an unpredictable risk of developing cardiotoxicity. Cardiotoxicity due to cancer treatment, as well as cancer progression, has been linked to autophagy dysregulation. Modulating autophagy has been further proposed as a therapeutic treatment for both cancer and cardiovascular disorders. The safe and effective use of autophagy modulation as a cardioprotective strategy during cancer treatment especially requires careful consideration and experimentation to minimize the impact on cancer treatment. We focus here on recent advances in targeted autophagy modulation strategies that utilize interdisciplinary approaches in biomedical sciences and are potentially translatable to treat cardiotoxicity and improve cancer treatment outcomes. This review highlights non-small molecule autophagy modulators to enhance targeted therapy, nanomedicine for autophagy modulation and monitoring, and in vitro models and future experiments needed to bring novel autophagy discoveries from basic research to clinical translation.
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Affiliation(s)
- Lauren A Ling
- Molecular Cardiology Research Institute, Tufts Medical Center, 800 Washington Street, #80, Boston, MA 02111, USA
- School of Medicine, Tufts University, 145 Harrison Avenue, Boston, MA 02111, USA
| | - Asma Boukhalfa
- Molecular Cardiology Research Institute, Tufts Medical Center, 800 Washington Street, #80, Boston, MA 02111, USA
| | - Andrew H Kung
- Molecular Cardiology Research Institute, Tufts Medical Center, 800 Washington Street, #80, Boston, MA 02111, USA
| | - Vicky K Yang
- Cummings School of Veterinary Medicine, Tufts University, 200 Westboro Rd., North Grafton, MA 01536, USA
| | - Howard H Chen
- Molecular Cardiology Research Institute, Tufts Medical Center, 800 Washington Street, #80, Boston, MA 02111, USA
- School of Medicine, Tufts University, 145 Harrison Avenue, Boston, MA 02111, USA
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21
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Blasiak J, Pawlowska E, Helotera H, Ionov M, Derwich M, Kaarniranta K. Potential of autophagy in subretinal fibrosis in neovascular age-related macular degeneration. Cell Mol Biol Lett 2025; 30:54. [PMID: 40307700 PMCID: PMC12044759 DOI: 10.1186/s11658-025-00732-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 04/11/2025] [Indexed: 05/02/2025] Open
Abstract
Age-related macular degeneration (AMD) is an eye disease that can lead to legal blindness and vision loss. In its advanced stages, it is classified into dry and neovascular AMD. In neovascular AMD, the formation of new blood vessels disrupts the structure of the retina and induces an inflammatory response. Treatment for neovascular AMD involves antibodies and fusion proteins targeting vascular endothelial growth factor A (VEGFA) and its receptors to inhibit neovascularization and slow vision loss. However, a fraction of patients with neovascular AMD do not respond to therapy. Many of these patients exhibit a subretinal fibrotic scar. Thus, retinal fibrosis may contribute to resistance against anti-VEGFA therapy and the cause of irreversible vision loss in neovascular AMD patients. Retinal pigment epithelium cells, choroidal fibroblasts, and retinal glial cells are crucial in the development of the fibrotic scar as they can undergo a mesenchymal transition mediated by transforming growth factor beta and other molecules, leading to their transdifferentiation into myofibroblasts, which are key players in subretinal fibrosis. Autophagy, a process that removes cellular debris and contributes to the pathogenesis of AMD, regardless of its type, may be stimulated by epithelial-mesenchymal transition and later inhibited. The mesenchymal transition of retinal cells and the dysfunction of the extracellular matrix-the two main aspects of fibrotic scar formation-are associated with impaired autophagy. Nonetheless, the causal relationship between autophagy and subretinal fibrosis remains unknown. This narrative/perspective review presents information on neovascular AMD, subretinal fibrosis, and autophagy, arguing that impaired autophagy may be significant for fibrosis-related resistance to anti-VEGFA therapy in neovascular AMD.
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Affiliation(s)
- Janusz Blasiak
- Faculty of Medicine, Collegium Medicum, Mazovian Academy in Plock, 09-402, Plock, Poland.
| | - Elzbieta Pawlowska
- Department of Pediatric Dentistry, Medical University of Lodz, 92-217, Lodz, Poland
| | - Hanna Helotera
- Department of Ophthalmology, University of Eastern Finland, 70210, Kuopio, Finland
| | - Maksim Ionov
- Faculty of Health Sciences, Mazovian Academy in Plock, 09-402, Plock, Poland
| | - Marcin Derwich
- Department of Pediatric Dentistry, Medical University of Lodz, 92-217, Lodz, Poland
| | - Kai Kaarniranta
- Department of Ophthalmology, University of Eastern Finland, 70210, Kuopio, Finland
- Department of Ophthalmology, Kuopio University Hospital, 70210, Kuopio, Finland
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22
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Liu H, Wang X, Li B, Xiang Z, Zhao Y, Lu M, Lin Q, Zheng S, Guan T, Zhang Y, Hu Y. LncRNA HITT inhibits autophagy by attenuating ATG12-ATG5-ATG16L1 complex formation. Cancer Lett 2025; 616:217532. [PMID: 40021040 DOI: 10.1016/j.canlet.2025.217532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 02/02/2025] [Accepted: 02/03/2025] [Indexed: 03/03/2025]
Abstract
Dysregulated autophagy has been implicated in the pathogenesis of numerous diseases, including cancer. Despite extensive research on the underlying mechanisms of autophagy, the involvement of long non-coding RNAs (lncRNAs) remains poorly understood. Here, we demonstrate that a previously identified lncRNA, HITT (HIF-1α inhibitor at the translation level), is closely associated with biological processes such as autophagy through unbiased bioinformatic analysis. Subsequent studies demonstrate that HITT is increased by several autophagic stimuli, including PI-103, a potent inhibitor of PI3K and mTOR. This is caused by a reduction in the binding between HITT and AGO2, resulting in a reduction in the activity of miR-205 towards HITT degradation. Increased HITT then binds to a key autophagy protein, Autophagy-related 5 (ATG5), and inhibits autophagosome formation by preventing the formation of the ATG12-ATG5-ATG16L1 complex. This results in HITT sensitizing PI-103-mediated cell death both in vitro and in vivo in nude mice by attenuating protective autophagy. The data presented herein demonstrate that HITT is a newly identified RNA regulator of autophagy and that it can be used to sensitize the colon cancer response to cell death by blocking the protective autophagy.
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Affiliation(s)
- Hao Liu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province, 150001, China; Key Laboratory of Science and Engineering for the Multi-modal Prevention and Control of Major Chronic Diseases, Ministry of Industry and Information Technology, HIT Zhengzhou Research Institute, Zhengzhou, 450000, China
| | - Xingwen Wang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province, 150001, China
| | - Bolun Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province, 150001, China
| | - Zhiyuan Xiang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province, 150001, China; Key Laboratory of Science and Engineering for the Multi-modal Prevention and Control of Major Chronic Diseases, Ministry of Industry and Information Technology, HIT Zhengzhou Research Institute, Zhengzhou, 450000, China
| | - Yanan Zhao
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province, 150001, China
| | - Minqiao Lu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province, 150001, China; Key Laboratory of Science and Engineering for the Multi-modal Prevention and Control of Major Chronic Diseases, Ministry of Industry and Information Technology, HIT Zhengzhou Research Institute, Zhengzhou, 450000, China
| | - Qingyu Lin
- Key Laboratory of Science and Engineering for the Multi-modal Prevention and Control of Major Chronic Diseases, Ministry of Industry and Information Technology, HIT Zhengzhou Research Institute, Zhengzhou, 450000, China
| | - Shanliang Zheng
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province, 150001, China
| | - Tianqi Guan
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province, 150001, China; Key Laboratory of Science and Engineering for the Multi-modal Prevention and Control of Major Chronic Diseases, Ministry of Industry and Information Technology, HIT Zhengzhou Research Institute, Zhengzhou, 450000, China
| | - Yihong Zhang
- Department of Endocrinology, Heilongjiang Province Hospital, Harbin, Heilongjiang Province, 150001, China
| | - Ying Hu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province, 150001, China; Key Laboratory of Science and Engineering for the Multi-modal Prevention and Control of Major Chronic Diseases, Ministry of Industry and Information Technology, HIT Zhengzhou Research Institute, Zhengzhou, 450000, China.
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23
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Livieri T, Alfieri L, Giacomello E, Alempijević D, Petrovic T, Kolev YG, Radaelli D, Neri M, D’Errico S. Traumatic brain injury and autophagy: a pilot study about the immunohistochemical expression of LC3B, Beclin 1, p62, and LAMP2A in human autoptic samples. Front Mol Neurosci 2025; 18:1562954. [PMID: 40356869 PMCID: PMC12066584 DOI: 10.3389/fnmol.2025.1562954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 04/14/2025] [Indexed: 05/15/2025] Open
Abstract
Introduction Autophagy is a cellular stress response that has been shown in the literature to be active in cerebral cells after a traumatic brain injury (TBI). The aim of this study is to investigate the potential use of four proteins involved in autophagy (LC3B, Beclin 1, p62, and LAMP2A), as a forensic diagnostic marker for TBI. Methods We analyzed histological samples obtained from the frontal lobe of 10 subjects who died within 1 h of a TBI (Group A), 13 who died between 1 h and 32 days post-TBI (Group B), and a control group of 10 subjects who died without head trauma (Group C). Immunohistochemical (IHC) staining using anti-LC3B, anti-Beclin 1, anti-p62 and anti-LAMP2A antibodies was performed. Results and discussion The results show that LC3B staining was the only one that show a statistically significant difference between groups. In particular, the percentage of neurons displaying an autophagic pattern was calculated from six random acquisitions per subject, and the results were compared across groups using one way ANOVA. Significant differences were observed between Groups A and B, and between Groups B and C, with p-values of 0.0055 and 0.0035, respectively. While the difference between Groups A and C was not statistically significant (p-value of 0.9845). These findings suggest that LC3B may serve as a useful diagnostic marker for TBI in cases where death is not immediate and open the door for further research.
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Affiliation(s)
- Tommaso Livieri
- Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Letizia Alfieri
- Department of Medical Sciences, Section of Legal Medicine, University of Ferrara, Ferrara, Italy
| | - Emiliana Giacomello
- Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Djordje Alempijević
- Institute of Forensic Medicine “Milovan Milovanovic”, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Tijana Petrovic
- Institute of Forensic Medicine “Milovan Milovanovic”, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Yanko Georgiev Kolev
- Department of General Medicine, Forensic Medicine and Deontology, Medical University - Pleven, Pleven, Bulgaria
| | - Davide Radaelli
- Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Margherita Neri
- Department of Medical Sciences, Section of Legal Medicine, University of Ferrara, Ferrara, Italy
| | - Stefano D’Errico
- Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy
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24
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Bauer JR, Robinson TL, Strich R, Cooper KF. Quitting Your Day Job in Response to Stress: Cell Survival and Cell Death Require Secondary Cytoplasmic Roles of Cyclin C and Med13. Cells 2025; 14:636. [PMID: 40358161 PMCID: PMC12071894 DOI: 10.3390/cells14090636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Revised: 04/16/2025] [Accepted: 04/18/2025] [Indexed: 05/15/2025] Open
Abstract
Following unfavorable environmental cues, cells reprogram pathways that govern transcription, translation, and protein degradation systems. This reprogramming is essential to restore homeostasis or commit to cell death. This review focuses on the secondary roles of two nuclear transcriptional regulators, cyclin C and Med13, which play key roles in this decision process. Both proteins are members of the Mediator kinase module (MKM) of the Mediator complex, which, under normal physiological conditions, positively and negatively regulates a subset of stress response genes. However, cyclin C and Med13 translocate to the cytoplasm following cell death or cell survival cues, interacting with a host of cell death and cell survival proteins, respectively. In the cytoplasm, cyclin C is required for stress-induced mitochondrial hyperfission and promotes regulated cell death pathways. Cytoplasmic Med13 stimulates the stress-induced assembly of processing bodies (P-bodies) and is required for the autophagic degradation of a subset of P-body assembly factors by cargo hitchhiking autophagy. This review focuses on these secondary, a.k.a. "night jobs" of cyclin C and Med13, outlining the importance of these secondary functions in maintaining cellular homeostasis following stress.
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Affiliation(s)
| | | | | | - Katrina F. Cooper
- Department of Cell and Molecular Biology, School of Osteopathic Medicine, Rowan-Virtua College of Medicine and Life Sciences, Rowan University, Stratford, NJ 08084, USA; (J.R.B.); (T.L.R.); (R.S.)
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25
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Qin Y, Zhang J, Wang A, Sun W, Qin X, Qi F, Wang Y, Du L, Liu X, Sun H, Guo Z, Guo X. Multi-omics analysis of two rat models reveals potential role of vesicle transport and autophagy in right ventricular remodeling. Sci Rep 2025; 15:13401. [PMID: 40251385 PMCID: PMC12008301 DOI: 10.1038/s41598-025-98347-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 04/10/2025] [Indexed: 04/20/2025] Open
Abstract
Right ventricular failure as a severe consequence of pulmonary arterial hypertension (PAH) is an independent risk factor for poor prognosis, although the pathogenesis of right ventricular remodeling (RVR) remains unclear. Exploring the shared molecular pathways and key molecules in the right ventricle in monocrotaline (MCT) and pulmonary artery banding (PAB) rat models may reveal critical RVR mechanisms. Untargeted proteome and metabolome analysis were performed on the right ventricular myocardium of two RVR models (MCT-induced PAH rats and PAB-operated rats) to identify the altered proteins and metabolites, followed by validation using parallel reaction monitoring analysis and quantitative real-time polymerase chain reaction (qPCR). The multi-omics profiles of MCT and PAB rat models were compared to explore the key dysregulated molecules and pathways in RVR. Our proteomics study identified 25 shared RVR-altered differentially expressed proteins. Multiple common biological pathways were identified between PAB and MCT rat models, encompassing myocardial remodeling and energy metabolism alternation, etc. Various molecules and pathways related to vesicle transport and autophagy were identified, including nidogen-1, the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) signaling pathway, and the microautophagy pathway (all previously unreported in RVR). Glycerophospholipid metabolism was the sole statistically significant common metabolic pathway enriched by metabolomics. Underreported biological processes, including vesicle transport and autophagy, may contribute to the pathophysiology of PAH-induced RVR.
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Affiliation(s)
- Yuhan Qin
- Department of Cardiology, Department of Internal Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No 1. Shuaifuyuan, Dongcheng District, Beijing, China
| | - Jing Zhang
- Department of Cardiology, Department of Internal Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No 1. Shuaifuyuan, Dongcheng District, Beijing, China
| | - Aiwei Wang
- Core Facility of Instrument, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Wei Sun
- Core Facility of Instrument, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Xiaohan Qin
- Department of Cardiology, Department of Internal Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No 1. Shuaifuyuan, Dongcheng District, Beijing, China
| | - Feng Qi
- Core Facility of Instrument, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yufei Wang
- Department of Cardiology, Department of Internal Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No 1. Shuaifuyuan, Dongcheng District, Beijing, China
| | - Le Du
- Department of Anesthesiology, Peking University Third Hospital, Beijing, China
| | - Xiaoyan Liu
- Core Facility of Instrument, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Haidan Sun
- Core Facility of Instrument, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Zhengguang Guo
- Core Facility of Instrument, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
| | - Xiaoxiao Guo
- Department of Cardiology, Department of Internal Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No 1. Shuaifuyuan, Dongcheng District, Beijing, China.
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26
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Liu Q, Hao T, Yang B, Zhang J, Pan S, Wu C, Tang Y, Zhou Y, Zhao Z, Du J, Li Y, Mai K, Ai Q. Autophagy dysfunction links palmitic acid with macrophage inflammatory responses in large yellow croaker (Larimichthys crocea). FISH & SHELLFISH IMMUNOLOGY 2025; 163:110319. [PMID: 40209962 DOI: 10.1016/j.fsi.2025.110319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 04/07/2025] [Accepted: 04/07/2025] [Indexed: 04/12/2025]
Abstract
Autophagy is a cellular degradation process reliant on lysosome, crucial for preserving intracellular homeostasis. The key saturated fatty acid palmitic acid (PA) has been demonstrated to exert regulatory effects on autophagic activity in mammals. However, the precise impact of PA on autophagy and its role in fish remains incompletely understood. Thus, this study aimed to investigate the regulation of PA on autophagy and explore the role of autophagy in inflammatory responses triggered by PA in the head kidney macrophages of large yellow croaker. This study indicates that PA exposure can inhibit macrophage autophagy by reducing the expression of genes related to autophagy (e.g., beclin1, ulk1, and lc3), activating the negative regulator mTORC1 signaling pathway (p70S6K and S6), and hindering autophagic flux. This effect was observed to be amplified with increasing exposure time and concentration of PA. Similarly to the in vitro results, the palm oil (PO) diet significantly reduced autophagic activity in the head kidney of the croaker in vivo. Subsequent studies demonstrated that restoring autophagy led to a notable reduction in the expression of PA and PO-induced pro-inflammatory genes (il-1β, il-6, tnf-α, and cox-2), the activation of the MAPK signaling pathway (p38 and JNK), and the NLRP3 inflammasome levels, both in vitro and in vivo. In contrast, further inhibition of autophagy produced the opposite effect in vitro. In conclusion, this study demonstrates that PA exerts a dynamic inhibitory effect on autophagy in the head kidney macrophage, which in turn promotes PA-induced inflammatory responses. These findings provide valuable insights into how PA influences autophagy and inflammatory responses in fish immune cells, contributing to the theoretical framework for improving the use of vegetable oils in aquaculture.
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Affiliation(s)
- Qiangde Liu
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China
| | - Tingting Hao
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China
| | - Bingyuan Yang
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China
| | - Jinze Zhang
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China
| | - Shijie Pan
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China
| | - Caixia Wu
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China
| | - Yuhang Tang
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China
| | - Yan Zhou
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China
| | - Zengqi Zhao
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China
| | - Jianlong Du
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China
| | - Yueru Li
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China
| | - Kangsen Mai
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China
| | - Qinghui Ai
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) and Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, 5 Yushan Road, 266003, Qingdao, Shandong, PR China.
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27
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Tang M, Tu Y, Gong Y, Yang Q, Wang J, Zhang Z, Qin J, Niu S, Yi J, Shang Z, Chen H, Tang Y, Huang Q, Liu Y, Billadeau DD, Liu X, Dai L, Jia D. β-hydroxybutyrate facilitates mitochondrial-derived vesicle biogenesis and improves mitochondrial functions. Mol Cell 2025; 85:1395-1410.e5. [PMID: 40118051 DOI: 10.1016/j.molcel.2025.02.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 11/04/2024] [Accepted: 02/26/2025] [Indexed: 03/23/2025]
Abstract
Mitochondrial dynamics and metabolites reciprocally influence each other. Mitochondrial-derived vesicles (MDVs) transport damaged mitochondrial components to lysosomes or the extracellular space. While many metabolites are known to modulate mitochondrial dynamics, it is largely unclear whether they are involved in MDV generation. Here, we discovered that the major component of ketone body, β-hydroxybutyrate (BHB), improved mitochondrial functions by facilitating the biogenesis of MDVs. Mechanistically, BHB drove specific lysine β-hydroxybutyrylation (Kbhb) of sorting nexin-9 (SNX9), a key regulator of MDV biogenesis. Kbhb increased SNX9 interaction with inner mitochondrial membrane (IMM)/matrix proteins and promoted the formation of IMM/matrix MDVs. SNX9 Kbhb was not only critical for maintaining mitochondrial homeostasis in cells but also protected mice from alcohol-induced liver injury. Altogether, our research uncovers the fact that metabolites influence the formation of MDVs by directly engaging in post-translational modifications of key protein machineries and establishes a framework for understanding how metabolites regulate mitochondrial functions.
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Affiliation(s)
- Min Tang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Yingfeng Tu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Yanqiu Gong
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Qin Yang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Jinrui Wang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Zhenzhen Zhang
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Institute for Brain Research and Rehabilitation, and Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, China
| | - Junhong Qin
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Shenghui Niu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Jiamin Yi
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Zehua Shang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Hongyu Chen
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Yingying Tang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Qian Huang
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yanmei Liu
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Institute for Brain Research and Rehabilitation, and Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, China
| | - Daniel D Billadeau
- Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Xingguo Liu
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China
| | - Lunzhi Dai
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Da Jia
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China; Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
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Wu J, Xu W, Su Y, Wang GH, Ma JJ. Targeting chaperone-mediated autophagy in neurodegenerative diseases: mechanisms and therapeutic potential. Acta Pharmacol Sin 2025; 46:816-828. [PMID: 39548290 PMCID: PMC11950187 DOI: 10.1038/s41401-024-01416-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 10/21/2024] [Indexed: 11/17/2024]
Abstract
The pathological hallmarks of various neurodegenerative diseases including Parkinson's disease and Alzheimer's disease prominently feature the accumulation of misfolded proteins and neuroinflammation. Chaperone-mediated autophagy (CMA) has emerged as a distinct autophagic process that coordinates the lysosomal degradation of specific proteins bearing the pentapeptide motif Lys-Phe-Glu-Arg-Gln (KFERQ), a recognition target for the cytosolic chaperone HSC70. Beyond its role in protein quality control, recent research underscores the intimate interplay between CMA and immune regulation in neurodegeneration. In this review, we illuminate the molecular mechanisms and regulatory pathways governing CMA. We further discuss the potential roles of CMA in maintaining neuronal proteostasis and modulating neuroinflammation mediated by glial cells. Finally, we summarize the recent advancements in CMA modulators, emphasizing the significance of activating CMA for the therapeutic intervention in neurodegenerative diseases.
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Affiliation(s)
- Jin Wu
- Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215123, China.
| | - Wan Xu
- Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215123, China
| | - Ying Su
- Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215123, China
| | - Guang-Hui Wang
- Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
| | - Jing-Jing Ma
- Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215123, China.
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Huang X, Yan H, Xu Z, Yang B, Luo P, He Q. The inducible role of autophagy in cell death: emerging evidence and future perspectives. Cell Commun Signal 2025; 23:151. [PMID: 40140912 PMCID: PMC11948861 DOI: 10.1186/s12964-025-02135-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 03/02/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND Autophagy is a lysosome-dependent degradation pathway for recycling intracellular materials and removing damaged organelles, and it is usually considered a prosurvival process in response to stress stimuli. However, increasing evidence suggests that autophagy can also drive cell death in a context-dependent manner. The bulk degradation of cell contents and the accumulation of autophagosomes are recognized as the mechanisms of cell death induced by autophagy alone. However, autophagy can also drive other forms of regulated cell death (RCD) whose mechanisms are not related to excessive autophagic vacuolization. Notably, few reviews address studies on the transformation from autophagy to RCD, and the underlying molecular mechanisms are still vague. AIM OF REVIEW This review aims to summarize the existing studies on autophagy-mediated RCD, to elucidate the mechanism by which autophagy initiates RCD, and to comprehensively understand the role of autophagy in determining cell fate. KEY SCIENTIFIC CONCEPTS OF REVIEW This review highlights the prodeath effect of autophagy, which is distinct from the generally perceived cytoprotective role, and its mechanisms are mainly associated with the selective degradation of proteins or organelles essential for cell survival and the direct involvement of the autophagy machinery in cell death. Additionally, this review highlights the need for better manipulation of autophagy activation or inhibition in different pathological contexts, depending on clinical purpose.
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Affiliation(s)
- Xiangliang Huang
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Hao Yan
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Zhifei Xu
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Bo Yang
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- School of Medicine, Hangzhou City University, Hangzhou, 310015, China
| | - Peihua Luo
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, China.
| | - Qiaojun He
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
- School of Medicine, Hangzhou City University, Hangzhou, 310015, China.
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, China.
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30
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Liu J, Aye Y. Tools to Dissect Lipid Droplet Regulation, Players, and Mechanisms. ACS Chem Biol 2025; 20:539-552. [PMID: 40035358 PMCID: PMC11934092 DOI: 10.1021/acschembio.4c00835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 02/10/2025] [Accepted: 02/14/2025] [Indexed: 03/05/2025]
Abstract
Spurred by the authors' own recent discovery of reactive metabolite-regulated nexuses involving lipid droplets (LDs), this perspective discusses the latest knowledge and multifaceted approaches toward deconstructing the function of these dynamic organelles, LD-associated localized signaling networks, and protein players. Despite accumulating knowledge surrounding protein families and pathways of conserved importance for LD homeostasis surveillance and maintenance across taxa, much remains to be understood at the molecular level. In particular, metabolic stress-triggered contextual changes in LD-proteins' localized functions, crosstalk with other organelles, and feedback signaling loops and how these are specifically rewired in disease states remain to be illuminated with spatiotemporal precision. We hope this perspective promotes an increased interest in these essential organelles and innovations of new tools and strategies to better understand context-specific LD regulation critical for organismal health.
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Affiliation(s)
- Jinmin Liu
- University
of Oxford, Oxford OX1 3TA, United
Kingdom
| | - Yimon Aye
- University
of Oxford, Oxford OX1 3TA, United
Kingdom
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31
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Ravindran R, Gustafsson ÅB. Mitochondrial quality control in cardiomyocytes: safeguarding the heart against disease and ageing. Nat Rev Cardiol 2025:10.1038/s41569-025-01142-1. [PMID: 40113864 DOI: 10.1038/s41569-025-01142-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/17/2025] [Indexed: 03/22/2025]
Abstract
Mitochondria are multifunctional organelles that are important for many different cellular processes, including energy production and biosynthesis of fatty acids, haem and iron-sulfur clusters. Mitochondrial dysfunction leads to a disruption in these processes, the generation of excessive reactive oxygen species, and the activation of inflammatory and cell death pathways. The consequences of mitochondrial dysfunction are particularly harmful in energy-demanding organs such as the heart. Loss of terminally differentiated cardiomyocytes leads to cardiac remodelling and a reduced ability to sustain contraction. Therefore, cardiomyocytes rely on multilayered mitochondrial quality control mechanisms to maintain a healthy population of mitochondria. Mitochondrial chaperones protect against protein misfolding and aggregation, and resident proteases eliminate damaged proteins through proteolysis. Irreparably damaged mitochondria can also be degraded through mitochondrial autophagy (mitophagy) or ejected from cells inside vesicles. The accumulation of dysfunctional mitochondria in cardiomyocytes is a hallmark of ageing and cardiovascular disease. This accumulation is driven by impaired mitochondrial quality control mechanisms and contributes to the development of heart failure. Therefore, there is a strong interest in developing therapies that directly target mitochondrial quality control in cardiomyocytes. In this Review, we discuss the current knowledge of the mechanisms involved in regulating mitochondrial quality in cardiomyocytes, how these pathways are altered with age and in disease, and the therapeutic potential of targeting mitochondrial quality control pathways in cardiovascular disease.
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Affiliation(s)
- Rishith Ravindran
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
| | - Åsa B Gustafsson
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
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32
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Liu Z, Peng H, Liu P, Duan F, Yang Y, Li P, Li Z, Wu J, Chang J, Shang D, Tian Q, Zhang J, Xie Y, Liu Z, An Y. Deciphering significances of autophagy in the development and metabolism of adipose tissue. Exp Cell Res 2025; 446:114478. [PMID: 39978716 DOI: 10.1016/j.yexcr.2025.114478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 02/17/2025] [Accepted: 02/17/2025] [Indexed: 02/22/2025]
Abstract
The mechanisms of adipose tissue activation and inactivation have been a hot topic of research in the last decade, from which countermeasures have been attempted to be found against obesity as well as other lipid metabolism-related diseases, such as type 2 diabetes mellitus and non-alcoholic fatty liver disease. Autophagy has been shown to be closely related to the regulation of adipocyte activity, which is involved in the whole process including white adipocyte differentiation/maturation and brown or beige adipocyte generation/activation. Dysregulation of autophagy in adipose tissue has been demonstrated to be associated with obesity. On this basis, we summarize the pathways and mechanisms of autophagy involved in the regulation of lipid metabolism and present a review of its pathophysiological roles in lipid metabolism-related diseases, in the hope of providing ideas for the treatment of these diseases.
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Affiliation(s)
- Zitao Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Haoyuan Peng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Pengfei Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Feiyi Duan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Yutian Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Pengkun Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Zhihao Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Jiaoyan Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Jiayi Chang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Dandan Shang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Qiwen Tian
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Jiawei Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Yucheng Xie
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Zhenzhen Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Yang An
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China; Henan Provincial Research Center of Engineering Technology for Nuclear Protein Medical Detection, Zhengzhou Health College, Zhengzhou, 450064, China.
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33
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Shao J, Xie S, Hong S, Qian L. Autophagy-Mediated Targeted Protein Degradation. ChemMedChem 2025; 20:e202400866. [PMID: 39672806 DOI: 10.1002/cmdc.202400866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 12/10/2024] [Accepted: 12/13/2024] [Indexed: 12/15/2024]
Abstract
Autophagy is an evolutionarily conserved turnover process in eukaryotes, mediating the delivery of various cellular components to lysosomes for degradation and facilitating the recycling of the breakdown products to maintain homeostasis. By harnessing this powerful autophagy-lysosomal degradation system, strategies for targeted protein degradation (TPD) have been emerging to remove specific disease-related proteins (both intracellular and cell-surface proteins) for complete elimination of their functions, bringing new insights to drug discovery. Herein, we give a brief introduction on how autophagy works followed by a focus on available small-molecule and macromolecule-based strategies for TPD mediated by autophagy.
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Affiliation(s)
- Jinning Shao
- Institute of Drug Metabolism and Pharmaceutical Analysis, Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Shangzhi Xie
- Institute of Drug Metabolism and Pharmaceutical Analysis, Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Shurui Hong
- Institute of Drug Metabolism and Pharmaceutical Analysis, Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Linghui Qian
- Institute of Drug Metabolism and Pharmaceutical Analysis, Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China
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34
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Liu T, Niu J, Huang Y, Chen H, Wu Y, Xu Y. Ultrastructural evidence for the activation of autophagy and analysis of the protective role of autophagy in goat spermatozoa under liquid storage. Front Vet Sci 2025; 12:1543459. [PMID: 40151572 PMCID: PMC11948349 DOI: 10.3389/fvets.2025.1543459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 02/28/2025] [Indexed: 03/29/2025] Open
Abstract
Liquid storage of semen is a widely used technology for promoting genetic improvement in goat breeding. The short shelf life of spermatozoa greatly limits the application of liquid storage, which urgently needs to explore the underlying regulatory factors. Autophagy as a cellular catabolic process plays critical roles in eliminating damaged material, that thus protects the function and fertilizing ability of spermatozoa. Nevertheless, the regulatory mechanisms of autophagy in goat spermatozoa under liquid storage remain unclear. In this study, the typical morphologic abnormalities and ultrastructural changes in goat spermatozoa, such as plasma membrane swollen and shrunken, acrosome exfoliation, and axoneme exposure, were observed after liquid storage at 4°C. Moreover, assessment of the formation of autophagy in liquid-stored goat spermatozoa was performed by a morphological "gold standard" of electron microscopy. Notably, a large number of vesicles with double-membrane structure indicating autophagosome were found to surround the aberrant spermatozoa, suggesting the activation of autophagy. Several proteins, such as LC3, ATG5, and p62, exhibited differential expression after liquid storage, which further validated the occurrence of autophagy in liquid-stored goat spermatozoa. Furthermore, chloroquine treatment was used to inhibit the autophagy of spermatozoa, which caused a significantly decrease in the quality of liquid-stored spermatozoa, including motility, viability, plasma membrane integrity, and acrosome integrity. Significant increase in ROS and MDA levels of spermatozoa and significant decrease in Ca2+ influx and protein tyrosine phosphorylation of spermatozoa were also detected after chloroquine-induced autophagy inhibition. The ultrastructural observation of double-membrane autophagosome provides strong evidences for the activation of autophagy in goat spermatozoa under liquid storage. The inhibition of autophagy mediated by chloroquine indicated that autophagy plays vital roles in the survival of spermatozoa. These results facilitate understanding the activation of autophagy in spermatozoa and provide valuable references for uncovering the underlying regulatory mechanisms of liquid storage of goat spermatozoa.
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Affiliation(s)
- Tengfei Liu
- College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - Jincong Niu
- College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - Yuqi Huang
- College of Life Sciences, Northwest A&F University, Yangling, China
| | - Hong Chen
- College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - Yongjie Wu
- College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - Yongping Xu
- College of Veterinary Medicine, Northwest A&F University, Yangling, China
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35
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Li B, Ming H, Qin S, Nice EC, Dong J, Du Z, Huang C. Redox regulation: mechanisms, biology and therapeutic targets in diseases. Signal Transduct Target Ther 2025; 10:72. [PMID: 40050273 PMCID: PMC11885647 DOI: 10.1038/s41392-024-02095-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 10/09/2024] [Accepted: 11/21/2024] [Indexed: 03/09/2025] Open
Abstract
Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both the onset and progression of various diseases. Under physiological conditions, oxidative free radicals generated by the mitochondrial oxidative respiratory chain, endoplasmic reticulum, and NADPH oxidases can be effectively neutralized by NRF2-mediated antioxidant responses. These responses elevate the synthesis of superoxide dismutase (SOD), catalase, as well as key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption of this finely tuned equilibrium is closely linked to the pathogenesis of a wide range of diseases. Recent advances have broadened our understanding of the molecular mechanisms underpinning this dysregulation, highlighting the pivotal roles of genomic instability, epigenetic modifications, protein degradation, and metabolic reprogramming. These findings provide a foundation for exploring redox regulation as a mechanistic basis for improving therapeutic strategies. While antioxidant-based therapies have shown early promise in conditions where oxidative stress plays a primary pathological role, their efficacy in diseases characterized by complex, multifactorial etiologies remains controversial. A deeper, context-specific understanding of redox signaling, particularly the roles of redox-sensitive proteins, is critical for designing targeted therapies aimed at re-establishing redox balance. Emerging small molecule inhibitors that target specific cysteine residues in redox-sensitive proteins have demonstrated promising preclinical outcomes, setting the stage for forthcoming clinical trials. In this review, we summarize our current understanding of the intricate relationship between oxidative stress and disease pathogenesis and also discuss how these insights can be leveraged to optimize therapeutic strategies in clinical practice.
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Affiliation(s)
- Bowen Li
- Department of Biotherapy, Institute of Oxidative Stress Medicine, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, PR China
| | - Hui Ming
- Department of Biotherapy, Institute of Oxidative Stress Medicine, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, PR China
| | - Siyuan Qin
- Department of Biotherapy, Institute of Oxidative Stress Medicine, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, PR China
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, PR China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Jingsi Dong
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Zhongyan Du
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
- Key Laboratory of Blood-stasis-toxin Syndrome of Zhejiang Province, Hangzhou, China.
| | - Canhua Huang
- Department of Biotherapy, Institute of Oxidative Stress Medicine, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, PR China.
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, PR China.
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Ahmad I, Zhang J, Li R, Su W, Liu W, Wu Y, Khan I, Liu X, Li LF, Li S, Zheng YH. Murine Leukemia Virus GlycoGag Antagonizes SERINC5 via ER-phagy Receptor RETREG1. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.06.641798. [PMID: 40093084 PMCID: PMC11908239 DOI: 10.1101/2025.03.06.641798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Serine incorporator 5 (SERINC5) is a host restriction factor that targets certain enveloped viruses, including human immunodeficiency virus type 1 (HIV-1) and murine leukemia virus (MLV). It integrates into the viral envelope from the cell surface, inhibiting viral entry. SERINC5 is transported to the cell surface via polyubiquitination, while a single K130R mutation retains it in the cytoplasm. Both HIV-1 Nef and MLV glycoGag proteins antagonize SERINC5 by reducing its expression in producer cells. Here, we report that MLV glycoGag employs selective autophagy to downregulate SERINC5, demonstrating a more potent mechanism for decreasing its cell surface expression. Although glycoGag is a type II integral membrane protein, it primarily localizes to the cytoplasm and undergoes rapid proteasomal degradation. Employing the K130R mutant, we show that Nef, primarily associated with the plasma membrane, downregulates SERINC5 only after it has trafficked to the cell surface, whereas glycoGag can reduce its expression before reaching the plasma membrane while still in the cytoplasm. Nonetheless, an interaction with SERINC5 stabilizes and recruits glycoGag to the plasma membrane, enabling it to downregulate SERINC5 from the cell surface. Through affinity-purified mass spectrometry analysis combined with CRISPR/Cas9 knockouts, we find that glycoGag's activity depends on reticulophagy regulator 1 (RETREG1), an ER-phagy receptor. Further knockout experiments of critical autophagy genes demonstrate that glycoGag downregulates cytoplasmic SERINC5 via micro-ER-phagy. These findings provide crucial new insights into the ongoing arms race between retroviruses and SERINC5 during infection.
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Affiliation(s)
- Iqbal Ahmad
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Jing Zhang
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Rongrong Li
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Wenqiang Su
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Weiqi Liu
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - You Wu
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Ilyas Khan
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Xiaomeng Liu
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Lian-Feng Li
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Sunan Li
- State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Yong-Hui Zheng
- Department of Microbiology and Immunology, University of Illinois, Chicago, IL 60612, USA
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37
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Zhang R, Yu C, Zeh HJ, Kroemer G, Klionsky DJ, Tang D, Kang R. TAX1BP1-dependent autophagic degradation of STING1 impairs anti-tumor immunity. Autophagy 2025:1-22. [PMID: 40000606 DOI: 10.1080/15548627.2025.2471736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 12/02/2024] [Accepted: 02/21/2025] [Indexed: 02/27/2025] Open
Abstract
The activation of STING1 can lead to the production and secretion of cytokines, initiating antitumor immunity. Here, we screened an ion channel ligand library and identified tetrandrine, a bis-benzylisoquinoline alkaloid, as an immunological adjuvant that enhances antitumor immunity by preventing the autophagic degradation of the STING1 protein. This tetrandrine effect is independent of its known function as a calcium or potassium channel blocker. Instead, tetrandrine inhibits lysosomal function, impairing cathepsin maturation, and autophagic degradation. Proteomic analysis of lysosomes identified TAX1BP1 as a novel autophagic receptor for the proteolysis of STING1. TAX1BP1 recognizes STING1 through the physical interaction of its coiled-coil domain with the cyclic dinucleotide binding domain of STING1. Systematic mutation of lysine (K) residues revealed that K63-ubiquitination of STING1 at the K224 site ignites TAX1BP1-dependent STING1 degradation. Combined treatment with tetrandrine and STING1 agonists promotes antitumor immunity by converting "cold" pancreatic cancers into "hot" tumors. This process is associated with enhanced cytokine release and increased infiltration of cytotoxic T-cells into the tumor microenvironment. The antitumor immunity mediated by tetrandrine and STING1 agonists is limited by neutralizing antibodies to the type I interferon receptor or CD8+ T cells. Thus, these findings establish a potential immunotherapeutic strategy against pancreatic cancer by preventing the autophagic degradation of STING1.
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Affiliation(s)
- Ruoxi Zhang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Chunhua Yu
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Herbert J Zeh
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
- Department of Biology, Pôle de Biologie, Institut du Cancer Paris CARPEM, Paris, France
| | - Daniel J Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
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Lu D, Wu S, Wang X, Zhang J, Xu Y, Tao L, Shen X. Oxymatrine alleviates ALD-induced cardiac hypertrophy by regulating autophagy via activation Nrf2/SIRT3 signaling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 138:156389. [PMID: 39827815 DOI: 10.1016/j.phymed.2025.156389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 12/24/2024] [Accepted: 01/10/2025] [Indexed: 01/22/2025]
Abstract
BACKGROUND Cardiac hypertrophy is a prevalent early pathological manifestation in various cardiovascular diseases, lacking effective interventions to impede its progression. Although oxymatrine (OMT) has shown potential benefits for cardiac function, its therapeutic efficacy and mechanism in cardiac hypertrophy remain incompletely understood. Notably, mitochondrial damage and dysregulated autophagy are pivotal pathogenic mechanisms in cardiac hypertrophy. PURPOSE We investigate the pharmacological characteristics and mechanism of OMT in mitochondrial function and autophagy in cardiac hypertrophy. STUDY DESIGN AND METHODS A murine model of cardiac hypertrophy was induced by aldosterone in combination with high-salt drinking water, while primary cardiomyocyte hypertrophy was induced by aldosterone in vitro. Cardiac hypertrophy was assessed using echocardiography and histopathological staining. Autophagosomes and mitochondrial morphology were visualized by transmission electron microscopy. Levels of reactive oxygen species (ROS), malondialdehyde (MDA), and adenosine triphosphate (ATP) were quantified using commercial kits. The binding affinity of OMT with Nrf2 was assessed through molecular docking. Furthermore, adenovirus, agonists, and inhibitors were employed to modulate Nrf2, followed by quantitative real-time polymerase chain reaction (qRT-PCR), immunoblotting, co-immunoprecipitation, chromatin immunoprecipitation, immunohistochemistry, and cellular thermal shift assay. RESULTS OMT effectively attenuated aldosterone-induced cardiac hypertrophy both in vivo and in vitro. OMT promoted the activation of Nrf2, leading to elevated SIRT3 expression and enhanced autophagolysosome fusion, thereby modulating mitophagy and improving mitochondrial function. Moreover, the cardioprotective effects of OMT were abolished upon silencing or inhibition of Nrf2. OMT binds to Nrf2, facilitating its dissociation and nuclear translocation. CONCLUSION OMT activates Nrf2, consequently enhancing SIRT3 transcription, restoring autophagic flux, and preserving mitochondrial integrity, thereby mitigating aldosterone-induced cardiac hypertrophy. In summary, our study is the first to discover and confirm that OMT can stabilize Nrf2, promoting its activation and subsequently up-regulating SIRT3, which in turn facilitates mitochondrial autophagy. Additionally, PARKIN appears to play a key role in SIRT3-mediated regulation of mitophagy, warranting further investigation.
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Affiliation(s)
- Dingchun Lu
- The State Key Laboratory of Functions and Applications of Medicinal Plants (The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province (The high educational key laboratory of Guizhou province for natural medicianl Pharmacology and Druggability), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The Department of Pharmacology of Materia Medica, School of Pharmaceutical Sciences, Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China
| | - Shun Wu
- The State Key Laboratory of Functions and Applications of Medicinal Plants (The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province (The high educational key laboratory of Guizhou province for natural medicianl Pharmacology and Druggability), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The Department of Pharmacology of Materia Medica, School of Pharmaceutical Sciences, Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China
| | - Xueting Wang
- The State Key Laboratory of Functions and Applications of Medicinal Plants (The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province (The high educational key laboratory of Guizhou province for natural medicianl Pharmacology and Druggability), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The Department of Pharmacology of Materia Medica, School of Pharmaceutical Sciences, Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China
| | - Jian Zhang
- The State Key Laboratory of Functions and Applications of Medicinal Plants (The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province (The high educational key laboratory of Guizhou province for natural medicianl Pharmacology and Druggability), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The Department of Pharmacology of Materia Medica, School of Pharmaceutical Sciences, Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China
| | - Yini Xu
- The State Key Laboratory of Functions and Applications of Medicinal Plants (The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province (The high educational key laboratory of Guizhou province for natural medicianl Pharmacology and Druggability), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The Department of Pharmacology of Materia Medica, School of Pharmaceutical Sciences, Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China
| | - Ling Tao
- The State Key Laboratory of Functions and Applications of Medicinal Plants (The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province (The high educational key laboratory of Guizhou province for natural medicianl Pharmacology and Druggability), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The Department of Pharmacology of Materia Medica, School of Pharmaceutical Sciences, Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China.
| | - Xiangchun Shen
- The State Key Laboratory of Functions and Applications of Medicinal Plants (The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province (The high educational key laboratory of Guizhou province for natural medicianl Pharmacology and Druggability), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The Department of Pharmacology of Materia Medica, School of Pharmaceutical Sciences, Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China.
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Cooper KF. Cargo hitchhiking autophagy - a hybrid autophagy pathway utilized in yeast. Autophagy 2025; 21:500-512. [PMID: 39757721 PMCID: PMC11849947 DOI: 10.1080/15548627.2024.2447207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 12/16/2024] [Accepted: 12/22/2024] [Indexed: 01/07/2025] Open
Abstract
Macroautophagy is a catabolic process that maintains cellular homeostasis by recycling intracellular material through the use of double-membrane vesicles called autophagosomes. In turn, autophagosomes fuse with vacuoles (in yeast and plants) or lysosomes (in metazoans), where resident hydrolases degrade the cargo. Given the conservation of autophagy, Saccharomyces cerevisiae is a valuable model organism for deciphering molecular details that define macroautophagy pathways. In yeast, macroautophagic pathways fall into two subclasses: selective and nonselective (bulk) autophagy. Bulk autophagy is predominantly upregulated following TORC1 inhibition, triggered by nutrient stress, and degrades superfluous random cytosolic proteins and organelles. In contrast, selective autophagy pathways maintain cellular homeostasis when TORC1 is active by degrading damaged organelles and dysfunctional proteins. Here, selective autophagy receptors mediate cargo delivery to the vacuole. Now, two groups have discovered a new hybrid autophagy mechanism, coined cargo hitchhiking autophagy (CHA), that uses autophagic receptor proteins to deliver selected cargo to phagophores built in response to nutrient stress for the random destruction of cytosolic contents. In CHA, various autophagic receptors link their cargos to lipidated Atg8, located on growing phagophores. In addition, the sorting nexin heterodimer Snx4-Atg20 assists in the degradation of cargo during CHA, possibly by aiding the delivery of cytoplasmic cargos to phagophores and/or by delaying the closure of expanding phagophores. This review will outline this new mechanism, also known as Snx4-assisted autophagy, that degrades an assortment of cargos in yeast, including transcription factors, glycogen, and a subset of ribosomal proteins.
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Affiliation(s)
- Katrina F. Cooper
- Department of Cell and Molecular Biology, Virtua Health College of Medicine and Life Sciences, School of Osteopathic Medicine, Rowan University, Stratford, NJ, USA
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40
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Huang M, Cai J, Yang S, Zhao Q, Shao Z, Zhang F, Zhang Y, Cao A, Li D. Secernin-2 Stabilizes Histone Methyltransferase KMT2C to Suppress Progression and Confer Therapeutic Sensitivity to PARP Inhibition in Triple-Negative Breast Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2413280. [PMID: 39836524 PMCID: PMC11905051 DOI: 10.1002/advs.202413280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 12/24/2024] [Indexed: 01/23/2025]
Abstract
Triple-negative breast cancer (TNBC) is a difficulty and bottleneck in the clinical treatment of breast cancer due to a lack of effective therapeutic targets. Herein, we first report that secernin 2 (SCRN2), an uncharacterized gene in human cancer, acts as a novel tumor suppressor in TNBC to inhibit cancer progression and enhance therapeutic sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition both in vitro and in vivo. SCRN2 is downregulated in TNBC through chaperone-mediated autophagic degradation, and its downregulation is associated with poor patient prognosis. Moreover, SCRN2 impedes the proteasomal degradation of histone-lysine N-methyltransferase 2C (KMT2C) by recruiting Bcl2-associated athanogene 2 to block the interaction of KMT2C with E3 ubiquitin-protein ligase CHIP. Consistently, SCRN2 transcriptionally activates Bcl2-modifying factor by amplifying histone H3 monomethylation at lysine 4 at its enhancer, thereby inducing intrinsic apoptosis. Notably, KMT2C knockdown restores the impaired TNBC progression caused by SCRN2 overexpression both in vitro and in vivo. Furthermore, SCRN2 decreases the expression of key DNA repair-related genes and induces endogenous DNA damage, thus conferring therapeutic sensitivity of TNBC cells to PARP inhibition. Collectively, these findings identify SCRN2 as a novel suppressor of TNBC, reveal its mechanism of action, and highlight its potential role in TNBC therapy.
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Affiliation(s)
- Min‐Ying Huang
- Shanghai Cancer Center and Institutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghai200032China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032China
- Cancer Institute, Shanghai Medical CollegeFudan UniversityShanghai200032China
| | - Jia‐Yang Cai
- Department of Breast SurgeryShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Shao‐Ying Yang
- Cancer Institute, Shanghai Medical CollegeFudan UniversityShanghai200032China
| | - Qian Zhao
- Cancer Institute, Shanghai Medical CollegeFudan UniversityShanghai200032China
- Department of Breast SurgeryShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Zhi‐Min Shao
- Shanghai Cancer Center and Institutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghai200032China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032China
- Cancer Institute, Shanghai Medical CollegeFudan UniversityShanghai200032China
- Department of Breast SurgeryShanghai Medical CollegeFudan UniversityShanghai200032China
- Shanghai Key Laboratory of Breast CancerShanghai Medical CollegeFudan UniversityShanghai200032China
- Shanghai Key Laboratory of Radiation OncologyShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Fang‐Lin Zhang
- Cancer Institute, Shanghai Medical CollegeFudan UniversityShanghai200032China
| | - Yin‐Ling Zhang
- Cancer Institute, Shanghai Medical CollegeFudan UniversityShanghai200032China
| | - A‐Yong Cao
- Department of Breast SurgeryShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Da‐Qiang Li
- Shanghai Cancer Center and Institutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghai200032China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032China
- Cancer Institute, Shanghai Medical CollegeFudan UniversityShanghai200032China
- Department of Breast SurgeryShanghai Medical CollegeFudan UniversityShanghai200032China
- Shanghai Key Laboratory of Breast CancerShanghai Medical CollegeFudan UniversityShanghai200032China
- Shanghai Key Laboratory of Radiation OncologyShanghai Medical CollegeFudan UniversityShanghai200032China
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Wang L, Sooram B, Kumar R, Schedin‐Weiss S, Tjernberg LO, Winblad B. Tau degradation in Alzheimer's disease: Mechanisms and therapeutic opportunities. Alzheimers Dement 2025; 21:e70048. [PMID: 40109019 PMCID: PMC11923393 DOI: 10.1002/alz.70048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 02/05/2025] [Accepted: 02/05/2025] [Indexed: 03/22/2025]
Abstract
In Alzheimer's disease (AD), tau undergoes abnormal post-translational modifications and aggregations. Impaired intracellular degradation pathways further exacerbate the accumulation of pathological tau. A new strategy - targeted protein degradation - recently emerged as a modality in drug discovery where bifunctional molecules bring the target protein close to the degradation machinery to promote clearance. Since 2016, this strategy has been applied to tau pathologies and attracted broad interest in academia and the pharmaceutical industry. However, a systematic review of recent studies on tau degradation mechanisms is lacking. Here we review tau degradation mechanisms (the ubiquitin-proteasome system and the autophagy-lysosome pathway), their dysfunction in AD, and tau-targeted degraders, such as proteolysis-targeting chimeras and autophagy-targeting chimeras. We emphasize the need for a continuous exploration of tau degradation mechanisms and provide a future perspective for developing tau-targeted degraders, encouraging researchers to work on new treatment options for AD patients. HIGHLIGHTS: Post-translational modifications, aggregation, and mutations affect tau degradation. A vicious circle exists between impaired degradation pathways and tau pathologies. Ubiquitin plays an important role in complex degradation pathways. Tau-targeted degraders provide promising strategies for novel AD treatment.
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Affiliation(s)
- Lisha Wang
- Division of NeurogeriatricsDepartment of Neurobiology, Care Sciences and SocietyKarolinska InstitutetSolnaSweden
| | - Banesh Sooram
- Division of NeurogeriatricsDepartment of Neurobiology, Care Sciences and SocietyKarolinska InstitutetSolnaSweden
| | - Rajnish Kumar
- Division of NeurogeriatricsDepartment of Neurobiology, Care Sciences and SocietyKarolinska InstitutetSolnaSweden
- Department of Pharmaceutical Engineering & TechnologyIndian Institute of Technology (BHU)VaranasiIndia
| | - Sophia Schedin‐Weiss
- Division of NeurogeriatricsDepartment of Neurobiology, Care Sciences and SocietyKarolinska InstitutetSolnaSweden
| | - Lars O. Tjernberg
- Division of NeurogeriatricsDepartment of Neurobiology, Care Sciences and SocietyKarolinska InstitutetSolnaSweden
| | - Bengt Winblad
- Division of NeurogeriatricsDepartment of Neurobiology, Care Sciences and SocietyKarolinska InstitutetSolnaSweden
- Theme Inflammation and AgingKarolinska University HospitalHuddingeSweden
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42
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Gyurkovska V, Alvarado Cartagena YM, Murtazina R, Zhao SF, Ximenez de Olaso C, Segev N. Selective clearance of aberrant membrane proteins by TORC1-mediated micro-ER-phagy. Cell Rep 2025; 44:115282. [PMID: 39946230 PMCID: PMC11999474 DOI: 10.1016/j.celrep.2025.115282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 12/24/2024] [Accepted: 01/16/2025] [Indexed: 02/28/2025] Open
Abstract
Aberrant accumulation and clearance of membrane proteins is associated with disease. Membrane proteins are inserted first to the endoplasmic reticulum (ER). During normal growth, two quality control (QC) processes, ER-associated degradation and macro-ER-phagy, deliver misfolded and excess membrane proteins for degradation in the proteasome and lysosome, respectively. We show that in yeast during normal growth, ER-QC is constitutive, since none of the stress-induced signaling pathways-nutritional, proteotoxic, or heat-are involved. In mutant cells defective in ER-QC, misfolded or excess proteins accumulate and nutritional stress, but not proteotoxic or heat stress, can stimulate their clearance. Early during nutritional stress, clearance occurs in the lysosome through a selective micro-ER-phagy pathway dependent on the ubiquitin ligase Rsp5, its Ssh4 adaptor, and ESCRT. In contrast, only a fraction of normal membrane proteins is degraded much later via macro-autophagy. Because the pathways explored here are conserved, nutritional stress emerges as a possible way for clearing disease-associated membrane proteins.
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Affiliation(s)
- Valeriya Gyurkovska
- Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Yaneris M Alvarado Cartagena
- Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Rakhilya Murtazina
- Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Sarah F Zhao
- Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Candela Ximenez de Olaso
- Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Nava Segev
- Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
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Gao X, Xiong Y, Ma H, Zhou H, Liu W, Sun Q. Visualizing bulk autophagy in vivo by tagging endogenous LC3B. Autophagy 2025:1-17. [PMID: 39952286 DOI: 10.1080/15548627.2025.2457910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 01/16/2025] [Accepted: 01/20/2025] [Indexed: 02/17/2025] Open
Abstract
Macroautophagy/autophagy plays a crucial role in maintaining cellular and organismal health, making the measurement of autophagy flux in vivo essential for its study. Current tools often depend on the overexpression of autophagy probes. In this study, we developed a knock-in mouse model, termed tfLC3-KI, by inserting a tandem fluorescent tag coding sequence into the native Map1lc3b gene locus. We found that tfLC3-KI mice exhibit optimal expression of mRFP-eGFP-LC3B, allowing for convenient measurement of autophagic structures and flux at single-cell resolution, both in vivo and in primary cell cultures. Additionally, we compared autophagy in neurons and glial cells across various brain regions between tfLC3-KI mice and CAG-tfLC3 mice, the latter overexpressing the probe under the strong CMV promoter. Finally, we used tfLC3-KI mice to map the spatial and temporal dynamics of basal autophagy activity in the reproductive system. Our findings highlight the value of the tfLC3-KI mouse model for investigating autophagy flux in vivo and demonstrate the feasibility of tagging endogenous proteins to visualize autophagic structures and flux in both bulk and selective autophagy research in vivo.Abbreviation: BafA1: bafilomycin A1; CQ: chloroquine; EBSS: Earle's balanced salt solution; Es: elongating spermatids; HPF: hippocampalformation; HY: hypothalamus; LCs: leydig cells; OLF: olfactory areas; PepA: pepstatin A; Rs: round spermatids; SCs: sertoli cells; Spc: spermatocytes; Spg: spermatogonia; tfLC3: tandem fluorescently tagged mRFP-eGFP-LC3; TH: thalamus.
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Affiliation(s)
- Xiukui Gao
- Department of Respiratory and Critical Care Medicine, Center for Metabolism Research, The Fourth Affiliated Hospital of Zhejiang University School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Yue Xiong
- Department of Respiratory and Critical Care Medicine, Center for Metabolism Research, The Fourth Affiliated Hospital of Zhejiang University School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Hangbin Ma
- Department of Urology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Hao Zhou
- Department of Urology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Wei Liu
- Department of Respiratory and Critical Care Medicine, Center for Metabolism Research, The Fourth Affiliated Hospital of Zhejiang University School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Qiming Sun
- Department of Respiratory and Critical Care Medicine, Center for Metabolism Research, The Fourth Affiliated Hospital of Zhejiang University School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
- Department of Biochemistry, and Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Moreno-Blas D, Adell T, González-Estévez C. Autophagy in Tissue Repair and Regeneration. Cells 2025; 14:282. [PMID: 39996754 PMCID: PMC11853389 DOI: 10.3390/cells14040282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 02/01/2025] [Accepted: 02/13/2025] [Indexed: 02/26/2025] Open
Abstract
Autophagy is a cellular recycling system that, through the sequestration and degradation of intracellular components regulates multiple cellular functions to maintain cellular homeostasis and survival. Dysregulation of autophagy is closely associated with the development of physiological alterations and human diseases, including the loss of regenerative capacity. Tissue regeneration is a highly complex process that relies on the coordinated interplay of several cellular processes, such as injury sensing, defense responses, cell proliferation, differentiation, migration, and cellular senescence. These processes act synergistically to repair or replace damaged tissues and restore their morphology and function. In this review, we examine the evidence supporting the involvement of the autophagy pathway in the different cellular mechanisms comprising the processes of regeneration and repair across different regenerative contexts. Additionally, we explore how modulating autophagy can enhance or accelerate regeneration and repair, highlighting autophagy as a promising therapeutic target in regenerative medicine for the development of autophagy-based treatments for human diseases.
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Affiliation(s)
| | | | - Cristina González-Estévez
- Department of Genetics, Microbiology and Statistics, School of Biology and Institute of Biomedicine (IBUB), University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain; (D.M.-B.); (T.A.)
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Tozawa S, Takahashi H, Noguchi S, Takizawa T, Sakurai T, Ohkuchi A, Fujiwara H, Takizawa T. Upregulation of Autophagy During the Differentiation of Primary Human Term Cytotrophoblast Cells into Syncytial Cells: Ultrastructural Analysis. Int J Mol Sci 2025; 26:1321. [PMID: 39941088 PMCID: PMC11818441 DOI: 10.3390/ijms26031321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 02/16/2025] Open
Abstract
The villous trophoblast cells are of fundamental importance because they fulfill a variety of functions that are vital for the growth of the fetus and the maintenance of pregnancy. A simple in vitro villous trophoblast cell model that grows on standard tissue culture plates has been utilized for various functional studies on villous trophoblast cells. Despite the potential value of incorporating electron microscopy analysis in reports on functional analysis of primary human trophoblast cells, electron microscopy analysis is exclusively ancillary to functional analysis in previous publications. In the context of autophagy research of villous trophoblast cells using primary trophoblast cells, a detailed ultrastructural analysis of autophagy flux using electron microscopy is imperative; however, it has not been conducted to date. In this study, we isolated term villous trophoblast cells (i.e., cytotrophoblast cells, CTB cells) using the most up-to-date isolation method for isolating pure CTB cells from human term placenta and investigated the ultrastructural dynamic process of autophagy of cultured CTB cells by means of transmission electron microscopy. The initial 6 h culture resulted in CTB cell aggregation; however, the majority of CTB cells did not differentiate into syncytial cells. In contrast, after 72 h, CTB cells exhibited a promotion of differentiation into syncytial cells. The electron microscopy analysis revealed the upregulation of autophagy and visualized unique autophagic profiles during differentiation into syncytial cells, which exhibited perinuclear accumulation of extremely large autophagosomes/autolysosomes. This study provides novel insights into the reproductive biology of primary trophoblast cells, thereby demonstrating the substantial value of primary trophoblast cells as research resources.
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Affiliation(s)
- Shohei Tozawa
- Department of Molecular Medicine and Anatomy, Nippon Medical School, Tokyo 113-8602, Japan; (S.T.); (S.N.); (T.T.); (T.S.)
- Department of Obstetrics and Gynecology, Jichi Medical University, Tochigi 329-0498, Japan; (H.T.); (A.O.); (H.F.)
| | - Hironori Takahashi
- Department of Obstetrics and Gynecology, Jichi Medical University, Tochigi 329-0498, Japan; (H.T.); (A.O.); (H.F.)
| | - Syunya Noguchi
- Department of Molecular Medicine and Anatomy, Nippon Medical School, Tokyo 113-8602, Japan; (S.T.); (S.N.); (T.T.); (T.S.)
| | - Takami Takizawa
- Department of Molecular Medicine and Anatomy, Nippon Medical School, Tokyo 113-8602, Japan; (S.T.); (S.N.); (T.T.); (T.S.)
| | - Takanobu Sakurai
- Department of Molecular Medicine and Anatomy, Nippon Medical School, Tokyo 113-8602, Japan; (S.T.); (S.N.); (T.T.); (T.S.)
| | - Akihide Ohkuchi
- Department of Obstetrics and Gynecology, Jichi Medical University, Tochigi 329-0498, Japan; (H.T.); (A.O.); (H.F.)
| | - Hiroyuki Fujiwara
- Department of Obstetrics and Gynecology, Jichi Medical University, Tochigi 329-0498, Japan; (H.T.); (A.O.); (H.F.)
| | - Toshihiro Takizawa
- Department of Molecular Medicine and Anatomy, Nippon Medical School, Tokyo 113-8602, Japan; (S.T.); (S.N.); (T.T.); (T.S.)
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Singh R, Gaur SK, Nagar R, Kaul R. Insights into the different mechanisms of Autophagy and Apoptosis mediated by Morbilliviruses. Virology 2025; 603:110371. [PMID: 39742556 DOI: 10.1016/j.virol.2024.110371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 12/10/2024] [Accepted: 12/20/2024] [Indexed: 01/03/2025]
Abstract
Viruses are obligate intracellular parasites that have co-evolved with the host. During the course of evolution, viruses have acquired abilities to abrogate the host's immune responses by modulating the host proteins which play a pivotal role in various biological processes. One such process is the programmed cell death in virus-infected cells, which can occur via autophagy or apoptosis. Morbilliviruses are known to modulate both autophagy and apoptosis. Upon infecting a cell, the morbilliviruses can utilize autophagosomes as their nest and delay the host defense apoptotic response, and/or can promote apoptosis to escalate the virus dissemination. Moreover, there is an active interplay between these two pathways which eventually decides the fate of a virus-infected cell. Recent advances in our understanding of these processes provide a potential rationale to further explore morbilliviruses for therapeutic purposes.
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Affiliation(s)
- Rashmi Singh
- Department of Microbiology, University of Delhi South Campus, New Delhi, 110021, India
| | - Sharad Kumar Gaur
- Department of Microbiology, University of Delhi South Campus, New Delhi, 110021, India
| | - Rakhi Nagar
- Department of Microbiology, University of Delhi South Campus, New Delhi, 110021, India
| | - Rajeev Kaul
- Department of Microbiology, University of Delhi South Campus, New Delhi, 110021, India.
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Lv Y, Song B, Yang G, Wang Y, Wu Z, Si M, Yang Z, Chen H, Liu C, Li M, Zhang Y, Qiao Z, Wang L, Xu W. In Situ Transformable Nanoparticle Effectively Suppresses Bladder Cancer by Damaging Mitochondria and Blocking Mitochondrial Autophagy Flux. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2409425. [PMID: 39651805 PMCID: PMC11791963 DOI: 10.1002/advs.202409425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 11/26/2024] [Indexed: 12/11/2024]
Abstract
Tumor therapeutic strategies based on mitochondrial damage have become an emerging trend. However, the low drug delivery efficiency caused by lysosomal sequestration and the activation of protective mitochondrial autophagy severely restricts the therapeutic efficacy. Herein, an in situ transformable nanoparticle named KCKT is developed to promote lysosomal escape and directly damage mitochondria while blocking mitochondrial autophagy. KCKT exhibits acid responsiveness for precise self-assembly into nanofibers within the lysosomes of cancer cells. The massive accumulation of nanofibers and excessive production of reactive oxygen species (ROS) under sonodynamic therapy synergistically induce lysosomal damage. This facilitates the escape of nanofibers from lysosomal sequestration, thereby enhancing drug delivery. Subsequently, the escaped nanofibers specifically aggregate around the mitochondria for long-term retention and generate ROS under ultrasound irradiation to induce mitochondrial damage. Notably, due to lysosomal dysfunction, damaged mitochondria cannot be cleared by autophagy, further aggravating oxidative damage. These results reveal that KCKT effectively improves drug delivery and mitochondria-targeted therapy efficiency by blocking protective autophagy. These findings hold significant potential for advancing the field of mitochondria-targeted therapy.
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Affiliation(s)
- Yulin Lv
- NHC Key Laboratoryof Molecular Probes and Targeted TheranosticsHarbin Medical UniversityHarbin150001China
- Department of UrologyHarbin Medical University Cancer HospitalHarbin150001China
| | - Benli Song
- CAS Center for Excellence in NanoscienceCAS Key Laboratory for Biomedical Effects of Nanomaterials and NanosafetyNational Center for Nanoscience and Technology (NCNST) No. 11 BeiyitiaoZhongguancunBeijing100190China
| | - Guang Yang
- Department of NeurosurgerThe First Affiliated Hospital of Harbin Medical UniversityHarbin150001China
| | - Yuting Wang
- NHC Key Laboratoryof Molecular Probes and Targeted TheranosticsHarbin Medical UniversityHarbin150001China
- Key Laboratory of the Fourth Hospital of Harbin Medical UniversityHarbin150001China
| | - Zeyu Wu
- NHC Key Laboratoryof Molecular Probes and Targeted TheranosticsHarbin Medical UniversityHarbin150001China
- Key Laboratory of the Fourth Hospital of Harbin Medical UniversityHarbin150001China
| | - Minggui Si
- NHC Key Laboratoryof Molecular Probes and Targeted TheranosticsHarbin Medical UniversityHarbin150001China
- Key Laboratory of the Fourth Hospital of Harbin Medical UniversityHarbin150001China
| | - Zongzheng Yang
- NHC Key Laboratoryof Molecular Probes and Targeted TheranosticsHarbin Medical UniversityHarbin150001China
- Department of UrologyHarbin Medical University Cancer HospitalHarbin150001China
| | - Huilin Chen
- NHC Key Laboratoryof Molecular Probes and Targeted TheranosticsHarbin Medical UniversityHarbin150001China
- Department of UrologyHarbin Medical University Cancer HospitalHarbin150001China
| | - Chen Liu
- NHC Key Laboratoryof Molecular Probes and Targeted TheranosticsHarbin Medical UniversityHarbin150001China
- Department of UrologyHarbin Medical University Cancer HospitalHarbin150001China
| | - Min Li
- NHC Key Laboratoryof Molecular Probes and Targeted TheranosticsHarbin Medical UniversityHarbin150001China
- Key Laboratory of the Fourth Hospital of Harbin Medical UniversityHarbin150001China
| | - Yinshi Zhang
- NHC Key Laboratoryof Molecular Probes and Targeted TheranosticsHarbin Medical UniversityHarbin150001China
- Department of UrologyHarbin Medical University Cancer HospitalHarbin150001China
| | - Zengying Qiao
- CAS Center for Excellence in NanoscienceCAS Key Laboratory for Biomedical Effects of Nanomaterials and NanosafetyNational Center for Nanoscience and Technology (NCNST) No. 11 BeiyitiaoZhongguancunBeijing100190China
| | - Lu Wang
- NHC Key Laboratoryof Molecular Probes and Targeted TheranosticsHarbin Medical UniversityHarbin150001China
- Key Laboratory of the Fourth Hospital of Harbin Medical UniversityHarbin150001China
| | - Wanhai Xu
- NHC Key Laboratoryof Molecular Probes and Targeted TheranosticsHarbin Medical UniversityHarbin150001China
- Department of UrologyThe 2nd Affiliated Hospital of Harbin Medical UniversityHarbin150001China
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Bao Y, Ma Y, Huang W, Bai Y, Gao S, Xiu L, Xie Y, Wan X, Shan S, Chen C, Qu L. Regulation of autophagy and cellular signaling through non-histone protein methylation. Int J Biol Macromol 2025; 291:139057. [PMID: 39710032 DOI: 10.1016/j.ijbiomac.2024.139057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 12/06/2024] [Accepted: 12/19/2024] [Indexed: 12/24/2024]
Abstract
Autophagy is a highly conserved catabolic pathway that is precisely regulated and plays a significant role in maintaining cellular metabolic balance and intracellular homeostasis. Abnormal autophagy is directly linked to the development of various diseases, particularly immune disorders, neurodegenerative conditions, and tumors. The precise regulation of proteins is crucial for proper cellular function, and post-translational modifications (PTMs) are key epigenetic mechanisms in the regulation of numerous biological processes. Multiple proteins undergo PTMs that influence autophagy regulation. Methylation modifications on non-histone lysine and arginine residues have been identified as common PTMs critical to various life processes. This paper focused on the regulatory effects of non-histone methylation modifications on autophagy, summarizing related research on signaling pathways involved in autophagy-related non-histone methylation, and discussing current challenges and clinical significance. Our review concludes that non-histone methylation plays a pivotal role in the regulation of autophagy and its associated signaling pathways. Targeting non-histone methylation offers a promising strategy for therapeutic interventions in diseases related to autophagy dysfunction, such as cancer and neurodegenerative disorders. These findings provide a theoretical basis for the development of non-histone-methylation-targeted drugs for clinical use.
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Affiliation(s)
- Yongfen Bao
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Xianning 437000, China; School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning 437000, China
| | - Yaoyao Ma
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Xianning 437000, China; School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning 437000, China
| | - Wentao Huang
- Department of Physiology, Hunan Normal University School of Medicine, Changsha 410013, China
| | - Yujie Bai
- Department of Scientific Research and Education, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330000, China
| | - Siying Gao
- Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Luyao Xiu
- Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Yuyang Xie
- Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Xinrong Wan
- Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Shigang Shan
- School of Public Health and Nursing, Hubei University of Science and Technology, Hubei 437000, China
| | - Chao Chen
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Lihua Qu
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Xianning 437000, China; School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning 437000, China.
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49
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Zhu L, Liu Y, Wang K, Wang N. Regulated cell death in acute myocardial infarction: Molecular mechanisms and therapeutic implications. Ageing Res Rev 2025; 104:102629. [PMID: 39644925 DOI: 10.1016/j.arr.2024.102629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/22/2024] [Accepted: 12/03/2024] [Indexed: 12/09/2024]
Abstract
Acute myocardial infarction (AMI), primarily caused by coronary atherosclerosis, initiates a series of events that culminate in the obstruction of coronary arteries, resulting in severe myocardial ischemia and hypoxia. The subsequent myocardial ischemia/reperfusion (I/R) injury further aggravates cardiac damage, leading to a decline in heart function and the risk of life-threatening complications. The complex interplay of multiple regulated cell death (RCD) pathways plays a pivotal role in the pathogenesis of AMI. Each RCD pathway is orchestrated by a symphony of molecular regulatory mechanisms, highlighting the dynamic changes and critical roles of key effector molecules. Strategic disruption or inhibition of these molecular targets offers a tantalizing prospect for mitigating or even averting the onset of RCD, thereby limiting the extensive loss of cardiomyocytes and the progression of detrimental myocardial fibrosis. This review systematically summarizes the mechanisms underlying various forms of RCD, provides an in-depth exploration of the pathogenesis of AMI through the lens of RCD, and highlights a range of promising therapeutic targets that hold the potential to revolutionize the management of AMI.
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Affiliation(s)
- Lili Zhu
- Department of Pathology, Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yiyang Liu
- Department of Pathophysiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, Changsha, Hunan, China; National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan, China
| | - Kangkai Wang
- Department of Pathophysiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, Changsha, Hunan, China; National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan, China
| | - Nian Wang
- Department of Pathophysiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, Changsha, Hunan, China; National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan, China.
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50
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Liang X, Wang X, Zou X, Wang Q, Wang H, Yang C, Li Y, Liao L, Zhu Z, Wang Y, He L. The 2-aminoadipic acid (2-AAA) regulates grass carp ULK2 to inhibit GCRV replication. FISH & SHELLFISH IMMUNOLOGY 2025; 157:110109. [PMID: 39753154 DOI: 10.1016/j.fsi.2024.110109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 12/27/2024] [Accepted: 12/31/2024] [Indexed: 01/07/2025]
Abstract
Grass carp is an important commercial fish in China that is plagued by various diseases, especially the hemorrhagic disease induced by grass carp reovirus (GCRV). Autophagy, a highly conserved biological process among eukaryotes, is pivotal in maintaining cellular homeostasis and managing various stressors, including viral infections. Uncoordinated (Unc) 51-like kinase 2 (ULK2) is considered an initiator of the autophagic process. In this study, we successfully cloned and isolated the ULK2 gene from grass carp. We observed that its expression levels were markedly altered following exposure to GCRV or pathogen-associated molecular patterns (PAMPs). Overexpression of CiULK2 in grass carp ovary cells (GCO) promoted GCRV replication. Conversely, CiULK2 knockdown resulted in inhibited viral loads compared to the control group. Moreover, we also reveal that 2-aminoadipic acid (2-AAA), a representative autophagy related metabolite, can inhibit autophagy and viral replication. Notably, these roles of CiULK2 in autophagy and GCRV replication were reversed upon treatment with the 2-AAA. Collectively, our findings demonstrate the 2-AAA regulates CiULK2 to inhibit GCRV replication.
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Affiliation(s)
- Xinyu Liang
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xuyang Wang
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaowen Zou
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qian Wang
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hanyue Wang
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Cheng Yang
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China
| | - Yongming Li
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China
| | - Lanjie Liao
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China
| | - Zuoyan Zhu
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China
| | - Yaping Wang
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China; Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing, 100101, China
| | - Libo He
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
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