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Li X, Zhan F, Qiu G, Lu P, Shen Z, Qi Y, Wu M, Chu M, Feng J, Wen Z, Yao X, Wang A, Jin W, Zhang X, Liao J, Zhang J, Song M, Wang W, Wang X. MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-Dependent nuclear translocation and transcriptional activation of antioxidant genes. Redox Biol 2025; 84:103681. [PMID: 40403491 DOI: 10.1016/j.redox.2025.103681] [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: 04/10/2025] [Revised: 05/07/2025] [Accepted: 05/13/2025] [Indexed: 05/24/2025] Open
Abstract
Acute respiratory distress syndrome (ARDS) following cardiopulmonary bypass (CPB) is driven by oxidative stress during lung ischemia-reperfusion injury (LIRI). Mitochondrial-derived peptide MOTS-c has emerged as a regulator of mitochondrial-nuclear communication, yet its role in CPB-induced ARDS remains unclear. Here, we identify MOTS-c as a critical mediator of endothelial protection against LIRI through MYH9-dependent nuclear translocation and transcriptional activation of antioxidant genes. In rat LIRI models, endothelial cells exhibited the most significant MOTS-c upregulation, correlating with barrier preservation and reduced oxidative stress. Mechanistically, hypoxia-reoxygenation (HR) triggered reactive oxygen species (ROS)-dependent phosphorylation of MYH9 at Ser1943 via casein kinase II subunit alpha (CK2A), enabling MOTS-c binding to MYH9-γ-Actin complexes for nuclear transport. RNA sequencing (RNA-seq) combined with chromatin immunoprecipitation sequencing (ChIP-seq) revealed direct MOTS-c interaction with promoters of antioxidant genes (e.g., HMOX1, NQO1), which harbor antioxidant response elements (AREs). Clinically, serum MOTS-c increments within 24 h post-CPB (ΔMOTS-c) outperformed traditional biomarkers in predicting ARDS incidence, with multivariate models incorporating ΔMOTS-c achieving superior discriminative power (AUC = 0.885). Exogenous MOTS-c administration in rats attenuated lung injury by reducing oxidative damage, inflammation, and mortality, recapitulating endogenous protective mechanisms. Our findings establish MOTS-c as a dual-function molecule-acting via ROS-CK2A-MYH9 signaling to activate nuclear antioxidant defenses and serving as a prognostic biomarker for CPB-related complications. This study bridges mitochondrial dynamics, nuclear transcriptional regulation, and clinical outcomes, offering novel preventive avenues for IRI-associated pathologies.
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Affiliation(s)
- Xiangyu Li
- Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Faliang Zhan
- Department of Cardiothoracic Surgery, Yili Friendship Hospital, Yining, China
| | - Guangfeng Qiu
- Department of Respiratory and Critical Care Medicine, Yili Friendship Hospital, Yining, China
| | - Peng Lu
- Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Zihao Shen
- Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Yuanpu Qi
- Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Minchao Wu
- Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Mingyu Chu
- Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Jia Feng
- Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Ziang Wen
- Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Xin Yao
- Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Ao Wang
- Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Wanjun Jin
- Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Xiao Zhang
- Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Junjie Liao
- Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Jialin Zhang
- Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Meijuan Song
- Department of Geriatrics, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
| | - Wei Wang
- Mazankowski Alberta Heart Institute, University of Alberta, Canada.
| | - Xiaowei Wang
- Department of Cardiovascular Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China; Department of Cardiovascular Surgery, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China.
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Wu Y, Yang Y, Qin X, Zhang Z, Ullah M, Li Y, Zhang Z. Unfolded proteins in the mitochondria activate HRI and inhibit mitochondrial protein translation. Cell Signal 2024; 123:111353. [PMID: 39168261 DOI: 10.1016/j.cellsig.2024.111353] [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: 03/22/2024] [Revised: 08/04/2024] [Accepted: 08/17/2024] [Indexed: 08/23/2024]
Abstract
The mitochondrial unfolded protein response (UPRmt) is triggered through eIF2α phosphorylation in mammals. However, the mechanisms of UPRmt activation and the influence of eIF2α phosphorylation on mitochondrial protein translation remain unclear. In this study, we confirmed that the UPRmt is a rapid and specific stress response that occurs through pharmacological induction of eIF2α phosphorylation, along with the phosphorylation of eIF2α, ATF4, and CHOP. Moreover, with the upregulation of the expression of some chaperones, cytochrome P450 enzymes, and DDIT4, as determined by RNA-Seq and ribosome profiling, eIF2α phosphorylation was found to be essential for the expression of ATF4 and CHOP, after which ATF4 trafficked into the nucleus and initiated CHOP expression. In addition, the generation of ROS and mitochondrial morphology were not affected by the GTPP-induced UPRmt. Furthermore, we investigated the mechanism by which HRI kinase-mediated UPRmt is induced by mitochondrial unfolded proteins via CRISPR-Cas9 technology, mitochondrial recruitment of HRI and interaction with other proteins. Moreover, we confirmed that mitochondrial protein translation and mitochondrial protein import were inhibited through eIF2α phosphorylation with the accumulation of unfolded mitochondrial proteins. These findings reveal the molecular mechanism of the UPRmt and its impact on cellular protein translation, which will offer novel insights into the functions of the UPRmt, including its implications for human disease and pathobiology.
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Affiliation(s)
- Yongshu Wu
- College of Animal Science and Technology College of Veterinary Medicine/Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province/Zhejiang Provincial Engineering Laboratory for Animal Health Inspection and Internet Technology/Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management/China-Australia Joint Laboratory for Animal Health Big Data Analytics, Zhejiang A&F University, Hangzhou 311300, China
| | - Yang Yang
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, Gansu, China
| | - Xiaodong Qin
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, Gansu, China
| | - Zhixiong Zhang
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, Gansu, China
| | - Munib Ullah
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, Gansu, China
| | - Yanmin Li
- College of Animal Science and Veterinary Medicine, Southwest Minzu University, Chengdu, Sichuan 610041, China.
| | - Zhidong Zhang
- College of Animal Science and Veterinary Medicine, Southwest Minzu University, Chengdu, Sichuan 610041, China.
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Chatterjee N, Sharma R, Kale PR, Trehanpati N, Ramakrishna G. Is the liver resilient to the process of ageing? Ann Hepatol 2024; 30:101580. [PMID: 39276981 DOI: 10.1016/j.aohep.2024.101580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 08/15/2024] [Accepted: 08/21/2024] [Indexed: 09/17/2024]
Abstract
The liver's unique regenerative capacity, immunotolerant feature, and polyploidy status distinguish it as a metabolic organ unlike any other in the body. Despite aging, the liver generally exhibits fewer pathological abnormalities than other organs (such as the kidney), maintaining its functions near-normal balanced manner. Subtle changes in the liver, including reduced blood flow, detoxification alterations, pseudo-capillarization, and lipofuscin deposition, may occur with chronological age. Research indicates that carefully selected liver grafts from octogenarian donors can perform well post-transplant, emphasizing instances where age doesn't necessarily compromise liver function. Notably, a recent report suggests that the liver is a youthful organ, with hepatocytes averaging an age of only 3 years. Despite the liver's impressive regenerative capabilities and cellular reserve, a lingering question persists: how does the liver maintain its youthful characteristic amidst the chronological aging of the entire organism? The various adaptive mechanism possibly include:(a) cellular hypertrophy to maintain physiological capacity even before proliferation initiates, (b) the "ploidy conveyor" as a genetic adaptation to endure aging-related stress, (c) sustained telomere length indicative of youthfulness (d) active extracellular matrix remodelling for normal cellular functioning, (e) Mitochondria-Endoplasmic Reticulum based metabolic adaptation and (c) cellular plasticity as fitness mechanisms for healthy aging. However, it is crucial to note that aged livers may have compromised regenerative capacity and chronic liver disease is often associated with declining function due to premature hepatocyte senescence. This review delves into varied cellular adaptations sustaining liver homeostasis with chronological aging and briefly explores the role of accelerated hepatocyte aging as a precursor to chronic liver disease.
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Affiliation(s)
- Nirupama Chatterjee
- Artemis Education and Research Foundation, Artemis Health Institute, Sector 51 Gurugram, India
| | - Rishabh Sharma
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana Amity Education Valley, Panchgaon, Manesar Gurugram, HR 122413, India
| | - Pratibha R Kale
- Department of Clinical Microbiology, Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, India
| | - Nirupma Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, India
| | - Gayatri Ramakrishna
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, India.
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Han X, Gao Y, Chen X, Bian C, Chen W, Yan F. Mitochondria UPR stimulation by pelargonidin-3-glucoside contributes to ameliorating lipid accumulation under copper exposure. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 942:173603. [PMID: 38821275 DOI: 10.1016/j.scitotenv.2024.173603] [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: 02/22/2024] [Revised: 05/24/2024] [Accepted: 05/26/2024] [Indexed: 06/02/2024]
Abstract
Intensification of copper pollution in the environment has led to its excessive accumulation in humans, causing oxidative stress and lipid metabolism disorders. It is necessary to look for effective targets and safe methods to alleviate copper toxicity. Pelargonidin-3-glucoside (Pg3G) is a natural anthocyanin with metal ion chelating ability and multiple physiological activities. In this study, lipid accumulation was investigated under copper exposure in Caenorhabditis elegans which can be improved by Pg3G. Transcriptome analysis revealed that differentially expressed genes are enriched in lipid metabolism and protein folding/degradation. Pg3G activated mitochondrial unfold protein response (UPRmt) to mitigate mitochondrial damage caused by copper and regulated the expression of genes involved in lipid absorption, transport, and synthesis, thereby reducing lipid levels in C. elegans. This improvement disappeared in the ubl-5 knockout strain, indicating that ubl-5 is one target of Pg3G. Meanwhile, in HepG2 cells, Pg3G enhanced the cellular antioxidant capacity by activating UPRmt for maintaining mitochondrial homeostasis, followed by inhibition of excessive lipid accumulation. Overall, these results suggested that UPRmt activation can be a strategy for mitigating lipid disorders induced by copper and Pg3G with excellent ability to resist oxidative stress specially targeted for ubl-5 has a promising application in controlling copper contamination.
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Affiliation(s)
- Xiao Han
- Department of Food Science and Nutrition, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China
| | - Yufang Gao
- Department of Food Science and Nutrition, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China
| | - Xinyi Chen
- Department of Food Science and Nutrition, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China
| | - Cheng Bian
- Department of Food Science and Nutrition, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China
| | - Wei Chen
- Department of Food Science and Nutrition, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China
| | - Fujie Yan
- Department of Food Science and Nutrition, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China.
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Sun Y, Jin L, Qin Y, Ouyang Z, Zhong J, Zeng Y. Harnessing Mitochondrial Stress for Health and Disease: Opportunities and Challenges. BIOLOGY 2024; 13:394. [PMID: 38927274 PMCID: PMC11200414 DOI: 10.3390/biology13060394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 05/26/2024] [Accepted: 05/27/2024] [Indexed: 06/28/2024]
Abstract
Mitochondria, essential organelles orchestrating cellular metabolism, have emerged as central players in various disease pathologies. Recent research has shed light on mitohormesis, a concept proposing an adaptive response of mitochondria to minor disturbances in homeostasis, offering novel therapeutic avenues for mitochondria-related diseases. This comprehensive review explores the concept of mitohormesis, elucidating its induction mechanisms and occurrence. Intracellular molecules like reactive oxygen species (ROS), calcium, mitochondrial unfolded proteins (UPRmt), and integrated stress response (ISR), along with external factors such as hydrogen sulfide (H2S), physical stimuli, and exercise, play pivotal roles in regulating mitohormesis. Based on the available evidence, we elucidate how mitohormesis maintains mitochondrial homeostasis through mechanisms like mitochondrial quality control and mitophagy. Furthermore, the regulatory role of mitohormesis in mitochondria-related diseases is discussed. By envisioning future applications, this review underscores the significance of mitohormesis as a potential therapeutic target, paving the way for innovative interventions in disease management.
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Affiliation(s)
| | | | | | | | | | - Ye Zeng
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China; (Y.S.); (L.J.); (Y.Q.); (Z.O.); (J.Z.)
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Xu WN, Zheng HL, Yang RZ, Sun YF, Peng BR, Liu C, Song J, Jiang SD, Zhu LX. The mitochondrial UPR induced by ATF5 attenuates intervertebral disc degeneration via cooperating with mitophagy. Cell Biol Toxicol 2024; 40:16. [PMID: 38472656 PMCID: PMC10933207 DOI: 10.1007/s10565-024-09854-9] [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: 10/27/2023] [Accepted: 02/27/2024] [Indexed: 03/14/2024]
Abstract
Intervertebral disc degeneration (IVDD) is an aging disease that results in a low quality of life and heavy socioeconomic burden. The mitochondrial unfolded protein response (UPRmt) take part in various aging-related diseases. Our research intents to explore the role and underlying mechanism of UPRmt in IVDD. Nucleus pulposus (NP) cells were exposed to IL-1β and nicotinamide riboside (NR) served as UPRmt inducer to treat NP cells. Detection of ATP, NAD + and NADH were used to determine the function of mitochondria. MRI, Safranin O-fast green and Immunohistochemical examination were used to determine the degree of IVDD in vivo. In this study, we discovered that UPRmt was increased markedly in the NP cells of human IVDD tissues than in healthy controls. In vitro, UPRmt and mitophagy levels were promoted in NP cells treated with IL-1β. Upregulation of UPRmt by NR and Atf5 overexpression inhibited NP cell apoptosis and further improved mitophagy. Silencing of Pink1 reversed the protective effects of NR and inhibited mitophagy induced by the UPRmt. In vivo, NR might attenuate the degree of IDD by activating the UPRmt in rats. In summary, the UPRmt was involved in IVDD by regulating Pink1-induced mitophagy. Mitophagy induced by the UPRmt might be a latent treated target for IVDD.
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Affiliation(s)
- Wen-Ning Xu
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
- Department of Clinic of Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200082, China
| | - Huo-Liang Zheng
- Department of Clinic of Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200082, China
| | - Run-Ze Yang
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Yuan-Fang Sun
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Bi-Rong Peng
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Chun Liu
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Jian Song
- Department of Clinic of Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200082, China.
- Department of Orthopedics, Huashan Hospital Fudan University, Shanghai, 200040, China.
| | - Sheng-Dan Jiang
- Department of Clinic of Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200082, China.
| | - Li-Xin Zhu
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
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Xu S, Liu H, Wang C, Deng Y, Xu B, Yang T, Liu W. Study of ATF4/CHOP axis-mediated mitochondrial unfolded protein response in neuronal apoptosis induced by methylmercury. Food Chem Toxicol 2023; 182:114190. [PMID: 37967789 DOI: 10.1016/j.fct.2023.114190] [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: 08/15/2023] [Revised: 10/18/2023] [Accepted: 11/08/2023] [Indexed: 11/17/2023]
Abstract
Methylmercury (MeHg) is a widely distributed environmental pollutant that can easily cross the blood-brain barrier and accumulate in the brain, thereby damaging the central nervous system. Studies have shown that MeHg-induced mitochondrial damage and apoptosis play a crucial role in its neurotoxic effects. Mitochondrial unfolded protein response (UPRmt) is indispensable to maintain mitochondrial protein homeostasis and ensure mitochondrial function, and the ATF4/CHOP axis is one of the signaling pathways to activate UPRmt. In this study, the role of the ATF4/CHOP axis-mediated UPRmt in the neurotoxicity of MeHg has been investigated by C57BL/6 mice and the HT22 cell line. We discovered that mice exposed to MeHg had abnormal neurobehavioral patterns. The pathological section showed a significant decrease in the number of neurons. MeHg also resulted in a reduction in mtDNA copy number and mitochondrial membrane potential (MMP). Additionally, the ATF4/CHOP axis and UPRmt were found to be significantly activated. Subsequently, we used siRNA to knock down ATF4 or CHOP and observed that the expression of UPRmt-related proteins and the apoptosis rate were significantly reduced. Our research showed that exposure to MeHg can over-activate the UPRmt through the ATF4/CHOP axis, leading to mitochondrial damage and ultimately inducing neuronal apoptosis.
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Affiliation(s)
- Si Xu
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Haihui Liu
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Chen Wang
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Yu Deng
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Bin Xu
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Tianyao Yang
- Department of Environmental Health, School of Public Health, China Medical University, China.
| | - Wei Liu
- Department of Environmental Health, School of Public Health, China Medical University, China.
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Park SC, Lee YS, Cho KA, Kim SY, Lee YI, Lee SR, Lim IK. What matters in aging is signaling for responsiveness. Pharmacol Ther 2023; 252:108560. [PMID: 37952903 DOI: 10.1016/j.pharmthera.2023.108560] [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: 06/04/2023] [Revised: 10/03/2023] [Accepted: 11/06/2023] [Indexed: 11/14/2023]
Abstract
Biological responsiveness refers to the capacity of living organisms to adapt to changes in both their internal and external environments through physiological and behavioral mechanisms. One of the prominent aspects of aging is the decline in this responsiveness, which can lead to a deterioration in the processes required for maintenance, survival, and growth. The vital link between physiological responsiveness and the essential life processes lies within the signaling systems. To devise effective strategies for controlling the aging process, a comprehensive reevaluation of this connecting loop is imperative. This review aims to explore the impact of aging on signaling systems responsible for responsiveness and introduce a novel perspective on intervening in the aging process by restoring the compromised responsiveness. These innovative mechanistic approaches for modulating altered responsiveness hold the potential to illuminate the development of action plans aimed at controlling the aging process and treating age-related disorders.
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Affiliation(s)
- Sang Chul Park
- The Future Life & Society Research Center, Advanced Institute of Aging Science, Chonnam National University, Gwangju 61469, Republic of Korea.
| | - Young-Sam Lee
- Department of New Biology, DGIST, Daegu 42988, Republic of Korea; Well Aging Research Center, Division of Biotechnology, DGIST, Daegu 42988, Republic of Korea.
| | - Kyung A Cho
- Department of Biochemistry, Chonnam National University Medical School, Jeollanam-do 58128, Republic of Korea
| | - Sung Young Kim
- Department of Biochemistry, Konkuk University School of Medicine, Seoul 05029, Republic of Korea
| | - Yun-Il Lee
- Well Aging Research Center, Division of Biotechnology, DGIST, Daegu 42988, Republic of Korea; Interdisciplinary Engineering Major, Department of Interdisciplinary Studies, DGIST, Daegu 42988, Republic of Korea
| | - Seung-Rock Lee
- Department of Biochemistry, Chonnam National University Medical School, Jeollanam-do 58128, Republic of Korea; Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - In Kyoung Lim
- Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon 16499, Republic of Korea
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González-Arzola K, Díaz-Quintana A. Mitochondrial Factors in the Cell Nucleus. Int J Mol Sci 2023; 24:13656. [PMID: 37686461 PMCID: PMC10563088 DOI: 10.3390/ijms241713656] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/31/2023] [Accepted: 08/31/2023] [Indexed: 09/10/2023] Open
Abstract
The origin of eukaryotic organisms involved the integration of mitochondria into the ancestor cell, with a massive gene transfer from the original proteobacterium to the host nucleus. Thus, mitochondrial performance relies on a mosaic of nuclear gene products from a variety of genomes. The concerted regulation of their synthesis is necessary for metabolic housekeeping and stress response. This governance involves crosstalk between mitochondrial, cytoplasmic, and nuclear factors. While anterograde and retrograde regulation preserve mitochondrial homeostasis, the mitochondria can modulate a wide set of nuclear genes in response to an extensive variety of conditions, whose response mechanisms often merge. In this review, we summarise how mitochondrial metabolites and proteins-encoded either in the nucleus or in the organelle-target the cell nucleus and exert different actions modulating gene expression and the chromatin state, or even causing DNA fragmentation in response to common stress conditions, such as hypoxia, oxidative stress, unfolded protein stress, and DNA damage.
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Affiliation(s)
- Katiuska González-Arzola
- Centro Andaluz de Biología Molecular y Medicina Regenerativa—CABIMER, Consejo Superior de Investigaciones Científicas—Universidad de Sevilla—Universidad Pablo de Olavide, 41092 Seville, Spain
- Departamento de Bioquímica Vegetal y Biología Molecular, Universidad de Sevilla, 41012 Seville, Spain
| | - Antonio Díaz-Quintana
- Departamento de Bioquímica Vegetal y Biología Molecular, Universidad de Sevilla, 41012 Seville, Spain
- Instituto de Investigaciones Químicas—cicCartuja, Universidad de Sevilla—C.S.I.C, 41092 Seville, Spain
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10
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Mitochondrial protein import and UPR mt in skeletal muscle remodeling and adaptation. Semin Cell Dev Biol 2023; 143:28-36. [PMID: 35063351 DOI: 10.1016/j.semcdb.2022.01.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 12/20/2021] [Accepted: 01/04/2022] [Indexed: 01/03/2023]
Abstract
The biogenesis of mitochondria requires the coordinated expression of the nuclear and the mitochondrial genomes. However, the vast majority of gene products within the organelle are encoded in the nucleus, synthesized in the cytosol, and imported into mitochondria via the protein import machinery, which permit the entry of proteins to expand the mitochondrial network. Once inside, proteins undergo a maturation and folding process brought about by enzymes comprising the unfolded protein response (UPRmt). Protein import and UPRmt activity must be synchronized and matched with mtDNA-encoded subunit synthesis for proper assembly of electron transport chain complexes to avoid proteotoxicity. This review discusses the functions of the import and UPRmt systems in mammalian skeletal muscle, as well as how exercise alters the equilibrium of these pathways in a time-dependent manner, leading to a new steady state of mitochondrial content resulting in enhanced oxidative capacity and improved muscle health.
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Otsuka K, Cornelissen G, Kubo Y, Shibata K, Mizuno K, Aiba T, Furukawa S, Ohshima H, Mukai C. Methods for assessing change in brain plasticity at night and psychological resilience during daytime between repeated long-duration space missions. Sci Rep 2023; 13:10909. [PMID: 37407662 DOI: 10.1038/s41598-023-36389-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/02/2023] [Indexed: 07/07/2023] Open
Abstract
This study was designed to examine the feasibility of analyzing heart rate variability (HRV) data from repeat-flier astronauts at matching days on two separate missions to assess any effect of repeated missions on brain plasticity and psychological resilience, as conjectured by Demertzi. As an example, on the second mission of a healthy astronaut studied about 20 days after launch, sleep duration lengthened, sleep quality improved, and spectral power (ms2) co-varying with activity of the salience network (SN) increased at night. HF-component (0.15-0.50 Hz) increased by 61.55%, and HF-band (0.30-0.40 Hz) by 92.60%. Spectral power of HRV indices during daytime, which correlate negatively with psychological resilience, decreased, HF-component by 22.18% and HF-band by 37.26%. LF-component and LF-band, reflecting activity of the default mode network, did not change significantly. During the second mission, 24-h acrophases of HRV endpoints did not change but the 12-h acrophase of TF-HRV did (P < 0.0001), perhaps consolidating the circadian system to help adapt to space by taking advantage of brain plasticity at night and psychological resilience during daytime. While this N-of-1 study prevents drawing definitive conclusions, the methodology used herein to monitor markers of brain plasticity could pave the way for further studies that could add to the present results.
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Affiliation(s)
- Kuniaki Otsuka
- Space Biomedical Research Group, Japan Aerospace Exploration Agency, Ibaraki, Japan.
- Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA.
- Tokyo Women's Medical University, Tokyo, Japan.
| | | | - Yutaka Kubo
- Tokyo Women's Medical University, Tokyo, Japan
| | | | - Koh Mizuno
- Space Biomedical Research Group, Japan Aerospace Exploration Agency, Ibaraki, Japan
- Faculty of Education, Tohoku Fukushi University, Miyagi, Japan
| | - Tatsuya Aiba
- Space Biomedical Research Group, Japan Aerospace Exploration Agency, Ibaraki, Japan
| | - Satoshi Furukawa
- Space Biomedical Research Group, Japan Aerospace Exploration Agency, Ibaraki, Japan
| | - Hiroshi Ohshima
- Space Biomedical Research Group, Japan Aerospace Exploration Agency, Ibaraki, Japan
| | - Chiaki Mukai
- Space Biomedical Research Group, Japan Aerospace Exploration Agency, Ibaraki, Japan
- Tokyo University of Science, Tokyo, Japan
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12
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Cui K, Li C, Fang G. Aerobic Exercise Delays Alzheimer's Disease by Regulating Mitochondrial Proteostasis in the Cerebral Cortex and Hippocampus. Life (Basel) 2023; 13:life13051204. [PMID: 37240849 DOI: 10.3390/life13051204] [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: 03/14/2023] [Revised: 04/25/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
In clinical practice, Alzheimer's disease (AD), as one of the main neurodegenerative diseases globally, currently has no cure. Recently, the delaying and improving effects of physical exercise on AD have gradually been confirmed; however, the specific mechanism involved needs further clarification. (1) Objective: Explore the mechanism aerobic exercise plays in delaying AD by regulating mitochondrial proteostasis and provide new theoretical bases for improving and delaying AD through aerobic exercise in the future. (2) Methods: Male APP/PS1 mice were randomly divided into a normal group (NG, n = 20), activation group (AG, n = 20), and inhibition group (SG, n = 20). Then, the mice in each group were randomly divided into control group and exercise group (n = 10 mice each), yielding the normal control group (CNG), normal exercise group (ENG), active control group (CAG), active exercise group (EAG), inhibitive control group (CSG), and inhibitive exercise group (ESG). After adaptive training, the mice in the exercise groups were trained on an aerobic treadmill for 12 weeks; we conducted behavioral tests and sampled the results. Then, quantitative real-time PCR (Q-PCR) and Western blot analysis were performed. (3) Results: In the Morris water maze (MWM) test, the latency was significantly reduced and the number of platform crossings was significantly increased in the CAG and ENG compared with the CNG, while the result of the CSG was contrary to this. Compared with the ENG, latency was significantly reduced and the number of platform crossings was significantly increased in the EAG, while the opposite occurred for ESG. Compared with the CAG, the latency was significantly reduced and the number of platform crossings was significantly increased in the EAG, while the results for CSG were contrary. In the step-down test, compared with the CNG, the latency was significantly increased and the number of errors was significantly reduced in the CAG and ENG, respectively, while the results for CSG were contrary. Compared with the ENG, the latency was significantly increased and the number of errors was significantly reduced in the EAG, while the results for ESG were contrary. Compared with the CAG, the latency was significantly increased and the number of errors was significantly reduced in the EAG, while the results for CSG were contrary. Mitochondrial unfolded protein reactions (UPRmt), mitochondrial autophagy, and mitochondrial protein import levels in each group of mice were detected using Q-PCR and Western blot experiments. Compared with the CNG, the UPRmt and mitochondrial autophagy levels in the CAG and ENG were significantly increased and the mitochondrial protein import levels were significantly reduced, while the results for the CSG were contrary. Compared with the ENG, the UPRmt and mitochondrial autophagy levels in the EAG were significantly increased and the mitochondrial protein import levels were significantly reduced, while the results for ESG were contrary. Compared with the CAG, the UPRmt and mitochondrial autophagy levels in the EAG were significantly increased and the mitochondrial protein import levels were significantly reduced, while the results for CSG were contrary. (4) Conclusions: Aerobic exercise can improve cognitive function levels and delay the symptoms of AD in APP/PS1 mice by regulating mitochondrial proteostasis.
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Affiliation(s)
- Kaiyin Cui
- China Institute of Sport Science, Beijing 100061, China
| | - Chaoyang Li
- China Institute of Sport Science, Beijing 100061, China
| | - Guoliang Fang
- China Institute of Sport Science, Beijing 100061, China
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13
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ATF5 Attenuates the Secretion of Pro-Inflammatory Cytokines in Activated Microglia. Int J Mol Sci 2023; 24:ijms24043322. [PMID: 36834738 PMCID: PMC9961550 DOI: 10.3390/ijms24043322] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 01/30/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
The highly dynamic changes in microglia necessary to achieve a rapid neuroinflammatory response require a supply of energy from mitochondrial respiration, which leads to the accumulation of unfolded mitochondrial proteins. We previously reported that microglial activation is correlated with the mitochondrial unfolded protein response (UPRmt) in a kaolin-induced hydrocephalus model, but we still do not know the extent to which these changes in microglia are involved in cytokine release. Here, we investigated the activation of BV-2 cells and found that treatment with lipopolysaccharide (LPS) for 48 h increased the secretion of pro-inflammatory cytokines. This increase was accompanied by a concurrent decrease in oxygen consumption rate (OCR) and mitochondrial membrane potential (MMP), in association with the up-regulation of the UPRmt. Inhibition of the UPRmt by knockdown of ATF5, a key upstream regulator of the UPRmt, using small-interfering RNA against ATF5 (siATF5) not only increased production of the pro-inflammatory cytokines, interleukin-6 (IL-6), IL-1β and tumor necrosis factor-α (TNF-α), but also decreased MMP. Our results suggest that ATF5-dependent induction of the UPRmt in microglia acts as a protective mechanism during neuroinflammation and may be a potential therapeutic target for reducing neuroinflammation.
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Wu JC, Huang CC, Wang PW, Chen TY, Hsu WM, Chuang JH, Chuang HC. ONC201 Suppresses Neuroblastoma Growth by Interrupting Mitochondrial Function and Reactivating Nuclear ATRX Expression While Decreasing MYCN. Int J Mol Sci 2023; 24:ijms24021649. [PMID: 36675163 PMCID: PMC9867473 DOI: 10.3390/ijms24021649] [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: 08/22/2022] [Revised: 01/03/2023] [Accepted: 01/07/2023] [Indexed: 01/18/2023] Open
Abstract
Neuroblastoma (NB) is characterized by several malignant phenotypes that are difficult to treat effectively without combination therapy. The therapeutic implication of mitochondrial ClpXP protease ClpP and ClpX has been verified in several malignancies, but is unknown in NB. Firstly, we observed a significant increase in ClpP and ClpX expression in immature and mature ganglion cells as compared to more malignant neuroblasts and less malignant Schwannian-stroma-dominant cell types in human neuroblastoma tissues. We used ONC201 targeting ClpXP to treat NB cells, and found a significant suppression of mitochondrial protease, i.e., ClpP and ClpX, expression and downregulation of mitochondrial respiratory chain subunits SDHB and NDUFS1. The latter was associated with a state of energy depletion, increased reactive oxygen species, and decreased mitochondrial membrane potential, consequently promoting apoptosis and suppressing cell growth of NB. Treatment of NB cells with ONC201 as well as the genetic attenuation of ClpP and ClpX through specific short interfering RNA (siRNA) resulted in the significant upregulation of the tumor suppressor alpha thalassemia/mental retardation X-linked (ATRX) and promotion of neurite outgrowth, implicating mitochondrial ClpXP proteases in MYCN-amplified NB cell differentiation. Furthermore, ONC201 treatment significantly decreased MYCN protein expression and suppressed tumor formation with the reactivation of ATRX expression in MYCN-amplified NB-cell-derived xenograft tumors. Taken together, ONC201 could be the potential agent to provide diversified therapeutic application in NB, particularly in NB with MYCN amplification.
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Affiliation(s)
- Jian-Ching Wu
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Chao-Cheng Huang
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Biobank and Tissue Bank, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Pei-Wen Wang
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Ting-Ya Chen
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Wen-Ming Hsu
- Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10617, Taiwan
| | - Jiin-Haur Chuang
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Department of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Hui-Ching Chuang
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Correspondence: ; Tel.: +886-7-7317123 (ext. 8896); Fax: +886-7-7311696
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15
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Xu WN, Liu C, Zheng HL, Xu HX, Yang RZ, Jiang SD, Zhu LX. Sesn2 Serves as a Regulator between Mitochondrial Unfolded Protein Response and Mitophagy in Intervertebral Disc Degeneration. Int J Biol Sci 2023; 19:571-592. [PMID: 36632468 PMCID: PMC9830501 DOI: 10.7150/ijbs.70211] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 10/30/2022] [Indexed: 01/04/2023] Open
Abstract
Mitochondrial unfold protein response (UPRmt) can induce mitophagy to protect cell from unfold protein. However, how UPRmt induces mitophagy to protect cell is not yet clear. Herein, Sesn2 was considered to be a key molecule that communicated UPRmt and mitophagy in the intervertebral disc. Silencing of Sesn2 was able to reverse the protective effects of Nicotinamide riboside (NR) on nucleus pulposus (NP) cells and inhibit mitophagy induced by UPRmt. UPRmt upregulated Sesn2 through Eif2ak4/eIF2α/Atf4, and further induced mitophagy. Sesn2 promoted the translocation of cytosolic Parkin and Sqstm1 to the defective mitochondria respectively, thereby enhancing mitophagy. The translocation of cytosolic Sqstm1 to the defective mitochondria was dependent on Parkin. The two functional domains of Sesn2 were necessary for the interaction of Sesn2 with Parkin and Sqstm1. The cytosolic interaction of Sesn2 between Parkin and Sqstm1 was independent on Pink1 (named as PINK1 in human) but the mitochondrial translocation was dependent on Pink1. Sesn2-/- mice showed a more severe degeneration and NR did not completely alleviate the intervertebral disc degeneration (IVDD) of Sesn2-/- mice. In conclusion, UPRmt could attenuate IVDD by upregulation of Sesn2-induced mitophagy. This study will help to further reveal the mechanism of Sesn2 regulating mitophagy, and open up new ideas for the prevention and treatment of IVDD.
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Affiliation(s)
- Wen-Ning Xu
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.,Department of Clinic of Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200082, China
| | - Chun Liu
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Huo-Liang Zheng
- Department of Clinic of Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200082, China
| | - Hai-Xia Xu
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Run-Ze Yang
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University
| | - Sheng-Dan Jiang
- Department of Clinic of Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200082, China.,✉ Corresponding authors: Sheng-Dan Jiang () and Li-Xin Zhu (); Tel: 13917924984; Postal Address: 510280
| | - Li-Xin Zhu
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.,✉ Corresponding authors: Sheng-Dan Jiang () and Li-Xin Zhu (); Tel: 13917924984; Postal Address: 510280
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16
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Tian X, Lou S, Shi R. From mitochondria to sarcopenia: role of 17β-estradiol and testosterone. Front Endocrinol (Lausanne) 2023; 14:1156583. [PMID: 37152937 PMCID: PMC10157222 DOI: 10.3389/fendo.2023.1156583] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 04/03/2023] [Indexed: 05/09/2023] Open
Abstract
Sarcopenia, characterized by a loss of muscle mass and strength with aging, is prevalent in older adults. Although the exact mechanisms underlying sarcopenia are not fully understood, evidence suggests that the loss of mitochondrial integrity in skeletal myocytes has emerged as a pivotal contributor to the complex etiology of sarcopenia. Mitochondria are the primary source of ATP production and are also involved in generating reactive oxygen species (ROS), regulating ion signals, and initiating apoptosis signals in muscle cells. The accumulation of damaged mitochondria due to age-related impairments in any of the mitochondrial quality control (MQC) processes, such as proteostasis, biogenesis, dynamics, and mitophagy, can contribute to the decline in muscle mass and strength associated with aging. Interestingly, a decrease in sex hormones (e.g., 17β-estradiol and testosterone), which occurs with aging, has also been linked to sarcopenia. Indeed, 17β-estradiol and testosterone targeted mitochondria and exhibited activities in regulating mitochondrial functions. Here, we overview the current literature on the key mechanisms by which mitochondrial dysfunction contribute to the development and progression of sarcopenia and the potential modulatory effects of 17β-estradiol and testosterone on mitochondrial function in this context. The advance in its understanding will facilitate the development of potential therapeutic agents to mitigate and manage sarcopenia.
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17
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Shilovsky GA, Ashapkin VV. Transcription Factor Nrf2 and Mitochondria - Friends or Foes in the Regulation of Aging Rate. BIOCHEMISTRY. BIOKHIMIIA 2022; 87:1477-1486. [PMID: 36717441 DOI: 10.1134/s0006297922120057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
At the first sight, the transcription factor Nrf2 as a master regulator of cellular antioxidant systems, and mitochondria as the main source of reactive oxygen species (ROS), should play the opposite roles in determining the pace of aging. However, since the causes of aging cannot be confined to the oxidative stress, the role of Nrf2 role cannot be limited to the regulation of antioxidant systems, and moreover, the role of mitochondria is not confined to the ROS production. In this review, we discussed only one aspect of this problem, namely, the molecular mechanisms of interaction between Nrf2 and mitochondria that influence the rate of aging and the lifespan. Experimental data accumulated so far show that the Nrf2 activity positively affects both the mitochondrial dynamics and mitochondrial quality control. Nrf2 influences the mitochondrial function through various mechanisms, e.g., regulation of nuclear genome-encoded mitochondrial proteins and changes in the balance of ROS or other metabolites that affect the functioning of mitochondria. In turn, multiple regulatory proteins functionally associated with the mitochondria affect the Nrf2 activity and even form mutual regulatory loops with Nrf2. We believe that these loops enable the fine-tuning of the cellular redox balance and, possibly, of the cellular metabolism as a whole. It has been commonly accepted for a long time that all mitochondrial regulatory signals are mediated by the nuclear genome-encoded proteins, whereas the mitochondrial genome encodes only a few respiratory chain proteins and two ribosomal RNAs. Relatively recently, mtDNA-encoded signal peptides have been discovered. In this review, we discuss the data on their interactions with the nuclear regulatory systems, first of all, Nrf2, and their possible involvement in the regulation of the aging rate. The interactions between regulatory cascades that link the programs ensuring the maintenance of cellular homeostasis and cellular responses to the oxidative stress are a significant part of both aging and anti-aging programs. Therefore, understanding these interactions will be of great help in searching for the molecular targets to counteract aging-associated diseases and aging itself.
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Affiliation(s)
- Gregory A Shilovsky
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia. .,Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia.,Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, 127051, Russia
| | - Vasily V Ashapkin
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia
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18
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ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle. Mol Metab 2022; 66:101623. [PMID: 36332794 PMCID: PMC9661517 DOI: 10.1016/j.molmet.2022.101623] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 10/19/2022] [Accepted: 10/24/2022] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVES The Mitochondrial Unfolded Protein Response (UPRmt) is a compartment-specific mitochondrial quality control (MQC) mechanism that uses the transcription factor ATF5 to induce the expression of protective enzymes to restore mitochondrial function. Acute exercise is a stressor that has the potential to temporarily disrupt organellar protein homeostasis, however, the roles of ATF5 and the UPRmt in maintaining basal mitochondrial content, function and exercise-induced MQC mechanisms in skeletal muscle are not known. METHODS ATF5 KO and WT mice were examined at rest or after a bout of acute endurance exercise. We measured protein content in whole muscle, nuclear, cytosolic and mitochondrial fractions, in addition to mRNA transcript levels in whole muscle. Using isolated mitochondria, we quantified rates of oxygen consumption and ROS emission to observe the effects of the absence of ATF5 on organelle function. RESULTS ATF5 KO mice exhibited a larger and less functional muscle mitochondrial pool, most likely a culmination of enhanced biogenesis via increased PGC-1α expression, and attenuated mitophagy. The absence of ATF5 resulted in a reduction in antioxidant proteins and increases in mitochondrial ROS emission, cytosolic cytochrome c, and the expression of mitochondrial chaperones. KO muscle also displayed enhanced exercise-induced stress kinase signaling, but a blunted mitophagic and UPRmt gene expression response, complemented by significant increases in the basal mRNA abundance and nuclear localization of ATF4. Instead of promoting its nuclear translocation, acute exercise caused the enrichment of ATF5 in mitochondrial fractions. We also identified PGC-1α as an additional regulator of the basal expression of UPRmt genes. CONCLUSION The transcription factor ATF5 retains a critical role in the maintenance of mitochondrial homeostasis and the appropriate response of muscle to acute exercise for the optimization of mitochondrial quality control.
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19
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Choi SE, Hwang Y, Lee SJ, Jung H, Shin TH, Son Y, Park S, Han SJ, Kim HJ, Lee KW, Lee G, Kemper JK, Song HK, Kang Y. Mitochondrial protease ClpP supplementation ameliorates diet-induced NASH in mice. J Hepatol 2022; 77:735-747. [PMID: 35421426 DOI: 10.1016/j.jhep.2022.03.034] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 02/18/2022] [Accepted: 03/21/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND & AIMS Mitochondrial dysfunction is considered a pathogenic linker in the development of non-alcoholic steatohepatitis (NASH). Inappropriate mitochondrial protein-quality control, possibly induced by insufficiency of the mitochondrial matrix caseinolytic protease P (ClpP), can potentially cause mitochondrial dysfunction. Herein, we aimed to investigate hepatic ClpP levels in a diet-induced model of NASH and determine whether supplementation of ClpP can ameliorate diet-induced NASH. METHODS NASH was induced by a high-fat/high-fructose (HF/HFr) diet in C57BL/6J mice. Stress/inflammatory signals were induced in mouse primary hepatocytes (MPHs) by treatment with palmitate/oleate (PA/OA). ClpP levels in hepatocytes were reduced using the RNAi-mediated gene knockdown technique but increased through the viral transduction of ClpP. ClpP activation was induced by administering a chemical activator of ClpP. RESULTS Hepatic ClpP protein levels in C57BL/6J mice fed a HF/HFr diet were lower than the levels in those fed a normal chow diet. PA/OA treatment also decreased the ClpP protein levels in MPHs. Overexpression or activation of ClpP reversed PA/OA-induced mitochondrial dysfunction and stress/inflammatory signal activation in MPHs, whereas ClpP knockdown induced mitochondrial dysfunction and stress/inflammatory signals in these cells. On the other hand, ClpP overexpression or activation improved HF/HFr-induced NASH characteristics such as hepatic steatosis, inflammation, fibrosis, and injury in the C57BL/6J mice, whereas ClpP knockdown further augmented steatohepatitis in mice fed a HF/HFr diet. CONCLUSIONS Reduced ClpP expression and subsequent mitochondrial dysfunction are key to the development of diet-induced NASH. ClpP supplementation through viral transduction or chemical activation represents a potential therapeutic strategy to prevent diet-induced NASH. LAY SUMMARY Western diets, containing high fat and high fructose, often induce non-alcoholic steatohepatitis (NASH). Mitochondrial dysfunction is considered pathogenically linked to diet-induced NASH. We observed that the mitochondrial protease ClpP decreased in the livers of mice fed a western diet and supplementation of ClpP ameliorated western diet-induced NASH.
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Affiliation(s)
- Sung-E Choi
- Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Yoonjung Hwang
- Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Soo-Jin Lee
- Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Hyunkyung Jung
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA 61801
| | - Tae Hwan Shin
- Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Youngho Son
- Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749; Department of Biomedical Science, The Graduate School, Ajou University, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Seokho Park
- Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749; Department of Biomedical Science, The Graduate School, Ajou University, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Seung Jin Han
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Hae Jin Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Kwan Woo Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Gwang Lee
- Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749
| | - Jongsook Kim Kemper
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA 61801
| | - Hyun Kyu Song
- School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea 136-701
| | - Yup Kang
- Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, Republic of Korea 443-749.
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20
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Kumar M, Sharma S, Haque M, Kumar J, Hathi UPS, Mazumder S. TLR22-Induced Pro-Apoptotic mtROS Abets UPRmt-Mediated Mitochondrial Fission in Aeromonas hydrophila-Infected Headkidney Macrophages of Clarias gariepinus. Front Immunol 2022; 13:931021. [PMID: 35860264 PMCID: PMC9292580 DOI: 10.3389/fimmu.2022.931021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/09/2022] [Indexed: 11/15/2022] Open
Abstract
Toll-like receptors (TLRs) are epitomized as the first line of defense against pathogens. Amongst TLRs, TLR22 is expressed in non-mammalian aquatic vertebrates, including fish. Using headkidney macrophages (HKM) of Clarias gariepinus, we reported the pro-apoptotic and microbicidal role of TLR22 in Aeromonas hydrophila infection. Mitochondria act as a central scaffold in the innate immune system. However, the precise molecular mechanisms underlying TLR22 signaling and mitochondrial involvement in A. hydrophila-pathogenesis remain unexplored in fish. The aim of the present study was to investigate the nexus between TLR22 and mitochondria in pro-apoptotic immune signaling circuitry in A. hydrophila-infected HKM. We report that TLR22-induced mitochondrial-Ca2+ [Ca2+]mt surge is imperative for mtROS production in A. hydrophila-infected HKM. Mitigating mtROS production enhanced intracellular bacterial replication implicating its anti-microbial role in A. hydrophila-pathogenesis. Enhanced mtROS triggers hif1a expression leading to prolonged chop expression. CHOP prompts mitochondrial unfolded protein response (UPRmt) leading to the enhanced expression of mitochondrial fission marker dnml1, implicating mitochondrial fission in A. hydrophila pathogenesis. Inhibition of mitochondrial fission reduced HKM apoptosis and increased the bacterial burden. Additionally, TLR22-mediated alterations in mitochondrial architecture impair mitochondrial function (ΔΨm loss and cytosolic accumulation of cyt c), which in turn activates caspase-9/caspase-3 axis in A. hydrophila-infected HKM. Based on these findings we conclude that TLR22 prompts mtROS generation, which activates the HIF-1α/CHOP signalosome triggering UPRmt-induced mitochondrial fragmentation culminating in caspase-9/-3-mediated HKM apoptosis and bacterial clearance.
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Affiliation(s)
- Manmohan Kumar
- Immunobiology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Shagun Sharma
- Immunobiology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Munira Haque
- Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, Delhi, India
| | - Jai Kumar
- Immunobiology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Umesh Prasad Sah Hathi
- Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, Delhi, India
| | - Shibnath Mazumder
- Immunobiology Laboratory, Department of Zoology, University of Delhi, Delhi, India
- Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, Delhi, India
- *Correspondence: Shibnath Mazumder,
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Cai G, Lin F, Wu D, Lin C, Chen H, Wei Y, Weng H, Chen Z, Wu M, Huang E, Ye Z, Ye Q. Rosmarinic Acid Inhibits Mitochondrial Damage by Alleviating Unfolded Protein Response. Front Pharmacol 2022; 13:859978. [PMID: 35652041 PMCID: PMC9149082 DOI: 10.3389/fphar.2022.859978] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
Mitochondria are essential organelles that perform important roles in cell biologies such as ATP synthesis, metabolic regulation, immunomodulatory, and apoptosis. Parkinson’s disease (PD) is connected with mitochondrial neuronal damage related to mitochondrial unfolded protein response (mtUPR). Rosmarinic acid (RA) is a naturally occurring hydroxylated polyphenolic chemical found in the Boraginaceae and the Labiatae subfamily Nepetoideae. This study looked into RA’s protective effect against mitochondrial loss in the substantia nigra (SN) caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the underlying mechanism associated with the mtUPR. Pretreatment with RA reduced motor impairments and dopaminergic neuronal degeneration in the SN of a mouse model injected with MPTP. Pretreatment of SH-SY5Y cells from cell viability loss, morphological damage, and oxidative stress. Furthermore, RA pre-injection suppressed MPTP-induced mtUPR, lowered the expression of HSPA9, HSPE1, CLPP, LONP1, and SIRT 4, and protected the MPTP-mice and SH-SY5Y cells from mitochondrial failure. These findings imply that RA can prevent Parkinson’s disease by preventing mitochondrial damage in dopaminergic neurons in Parkinson’s disease via alleviating mitochondrial unfolded protein response.
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Affiliation(s)
- Guoen Cai
- Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology, Institute of Clinical Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, China
| | - Fabin Lin
- Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology, Institute of Clinical Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, China
- Department of Clinical Medicine, Fujian Medical University, Fuzhou, China
| | - Dihang Wu
- Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology, Institute of Clinical Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, China
- Department of Clinical Medicine, Fujian Medical University, Fuzhou, China
| | - Chenxin Lin
- Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology, Institute of Clinical Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, China
- Department of Clinical Medicine, Fujian Medical University, Fuzhou, China
| | - Huiyun Chen
- Fujian Province Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Yicong Wei
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Huidan Weng
- Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology, Institute of Clinical Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, China
| | - Zhiting Chen
- Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology, Institute of Clinical Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, China
| | - Minxia Wu
- Public Technology Service Center, Fujian Medical University, Fuzhou, China
| | - En Huang
- Fujian Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Zucheng Ye
- Fujian Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
- *Correspondence: Zucheng Ye, ; Qinyong Ye,
| | - Qinyong Ye
- Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology, Institute of Clinical Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, China
- *Correspondence: Zucheng Ye, ; Qinyong Ye,
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22
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Suárez-Rivero JM, Pastor-Maldonado CJ, Romero-González A, Gómez-Fernandez D, Povea-Cabello S, Álvarez-Córdoba M, Villalón-García I, Talaverón-Rey M, Suárez-Carrillo A, Munuera-Cabeza M, Sánchez-Alcázar JA. Pterostilbene in Combination With Mitochondrial Cofactors Improve Mitochondrial Function in Cellular Models of Mitochondrial Diseases. Front Pharmacol 2022; 13:862085. [PMID: 35370630 PMCID: PMC8971666 DOI: 10.3389/fphar.2022.862085] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/03/2022] [Indexed: 12/13/2022] Open
Abstract
Mitochondrial diseases are genetic disorders caused by mutations in genes in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that encode mitochondrial structural or functional proteins. Although considered “rare” due to their low incidence, such diseases affect thousands of patients’ lives worldwide. Despite intensive research efforts, most mitochondrial diseases are still incurable. Recent studies have proposed the modulation of cellular compensatory pathways such as mitophagy, AMP-activated protein kinase (AMPK) activation or the mitochondrial unfolded protein response (UPRmt) as novel therapeutic approaches for the treatment of these pathologies. UPRmt is an intracellular compensatory pathway that signals mitochondrial stress to the nucleus for the activation of mitochondrial proteostasis mechanisms including chaperones, proteases and antioxidants. In this work a potentially beneficial molecule, pterostilbene (a resveratrol analogue), was identified as mitochondrial booster in drug screenings. The positive effects of pterostilbene were significantly increased in combination with a mitochondrial cocktail (CoC3) consisting of: pterostilbene, nicotinamide, riboflavin, thiamine, biotin, lipoic acid and l-carnitine. CoC3 increases sirtuins’ activity and UPRmt activation, thus improving pathological alterations in mutant fibroblasts and induced neurons.
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23
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Barba-Aliaga M, Alepuz P. Role of eIF5A in Mitochondrial Function. Int J Mol Sci 2022; 23:1284. [PMID: 35163207 PMCID: PMC8835957 DOI: 10.3390/ijms23031284] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/19/2022] [Accepted: 01/21/2022] [Indexed: 12/17/2022] Open
Abstract
The eukaryotic translation initiation factor 5A (eIF5A) is an evolutionarily conserved protein that binds ribosomes to facilitate the translation of peptide motifs with consecutive prolines or combinations of prolines with glycine and charged amino acids. It has also been linked to other molecular functions and cellular processes, such as nuclear mRNA export and mRNA decay, proliferation, differentiation, autophagy, and apoptosis. The growing interest in eIF5A relates to its association with the pathogenesis of several diseases, including cancer, viral infection, and diabetes. It has also been proposed as an anti-aging factor: its levels decay in aged cells, whereas increasing levels of active eIF5A result in the rejuvenation of the immune and vascular systems and improved brain cognition. Recent data have linked the role of eIF5A in some pathologies with its function in maintaining healthy mitochondria. The eukaryotic translation initiation factor 5A is upregulated under respiratory metabolism and its deficiency reduces oxygen consumption, ATP production, and the levels of several mitochondrial metabolic enzymes, as well as altering mitochondria dynamics. However, although all the accumulated data strongly link eIF5A to mitochondrial function, the precise molecular role and mechanisms involved are still unknown. In this review, we discuss the findings linking eIF5A and mitochondria, speculate about its role in regulating mitochondrial homeostasis, and highlight its potential as a target in diseases related to energy metabolism.
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Affiliation(s)
- Marina Barba-Aliaga
- Instituto de Biotecnología y Biomedicina (Biotecmed), Universitat de València, 46100 València, Spain
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas, Universitat de València, 46100 València, Spain
| | - Paula Alepuz
- Instituto de Biotecnología y Biomedicina (Biotecmed), Universitat de València, 46100 València, Spain
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Biológicas, Universitat de València, 46100 València, Spain
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24
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Lin YF, Sam J, Evans T. Sirt1 promotes tissue regeneration in zebrafish through regulating the mitochondrial unfolded protein response. iScience 2021; 24:103118. [PMID: 34622167 PMCID: PMC8479786 DOI: 10.1016/j.isci.2021.103118] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 08/12/2021] [Accepted: 09/09/2021] [Indexed: 11/16/2022] Open
Abstract
The mitochondrial unfolded protein response (UPRmt) is an organellar stress signaling pathway that functions to detect and restore disruption of mitochondrial proteostasis. The UPRmt is involved in a wide range of physiological and disease conditions, including aging, stem cell maintenance, innate immunity, neurodegeneration, and cancer. Here we report that the UPRmt is integral to zebrafish fin regeneration. Taking advantage of a novel zebrafish UPRmt reporter, we observed that UPRmt activation occurs in regenerating fin tissue shortly after injury. Through chemical and genetic approaches, we discovered that the Sirt1-UPRmt pathway, best known for its role in promoting lifespan extension, is crucial for fin regeneration. The metabolism of NAD+ is an important contributor to Sirt1 activity in this context. We propose that Sirt1 activation induces mitochondrial biogenesis in injured fin tissue, which leads to UPRmt activation and promotes tissue regeneration.
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Affiliation(s)
- Yi-Fan Lin
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, LC-708, New York, NY 10065, USA
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, 30013, Taiwan
- Department of Life Science, National Tsing Hua University, Hsinchu, 30013, Taiwan
| | - Jessica Sam
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, LC-708, New York, NY 10065, USA
| | - Todd Evans
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, LC-708, New York, NY 10065, USA
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25
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Gu LF, Chen JQ, Lin QY, Yang YZ. Roles of mitochondrial unfolded protein response in mammalian stem cells. World J Stem Cells 2021; 13:737-752. [PMID: 34367475 PMCID: PMC8316864 DOI: 10.4252/wjsc.v13.i7.737] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 05/13/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved adaptive mechanism for improving cell survival under mitochondrial stress. Under physiological and pathological conditions, the UPRmt is the key to maintaining intracellular homeostasis and proteostasis. Important roles of the UPRmt have been demonstrated in a variety of cell types and in cell development, metabolism, and immune processes. UPRmt dysfunction leads to a variety of pathologies, including cancer, inflammation, neurodegenerative disease, metabolic disease, and immune disease. Stem cells have a special ability to self-renew and differentiate into a variety of somatic cells and have been shown to exist in a variety of tissues. These cells are involved in development, tissue renewal, and some disease processes. Although the roles and regulatory mechanisms of the UPRmt in somatic cells have been widely reported, the roles of the UPRmt in stem cells are not fully understood. The roles and functions of the UPRmt depend on stem cell type. Therefore, this paper summarizes the potential significance of the UPRmt in embryonic stem cells, tissue stem cells, tumor stem cells, and induced pluripotent stem cells. The purpose of this review is to provide new insights into stem cell differentiation and tumor pathogenesis.
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Affiliation(s)
- Li-Fang Gu
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Jia-Qi Chen
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Qing-Yin Lin
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yan-Zhou Yang
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750001, Ningxia Hui Autonomous Region, China.
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26
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ATF5, a putative therapeutic target for the mitochondrial DNA 3243A > G mutation-related disease. Cell Death Dis 2021; 12:701. [PMID: 34262025 PMCID: PMC8280182 DOI: 10.1038/s41419-021-03993-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 06/29/2021] [Accepted: 07/01/2021] [Indexed: 12/29/2022]
Abstract
The mitochondrial DNA m.3243A > G mutation is well-known to cause a variety of clinical phenotypes, including diabetes, deafness, and osteoporosis. Here, we report isolation and expansion of urine-derived stem cells (USCs) from patients carrying the m.3243A > G mutation, which demonstrate bimodal heteroplasmy. USCs with high levels of m.3243A > G mutation displayed abnormal mitochondrial morphology and function, as well as elevated ATF5-dependent mitochondrial unfolded protein response (UPRmt), together with reduced Wnt/β-catenin signaling and osteogenic potentials. Knockdown of ATF5 in mutant USCs suppressed UPRmt, improved mitochondrial function, restored expression of GSK3B and WNT7B, and rescued osteogenic potentials. These results suggest that ATF5-dependent UPRmt could be a core disease mechanism underlying mitochondrial dysfunction and osteoporosis related to the m.3243A > G mutation, and therefore could be a novel putative therapeutic target for this genetic disorder.
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27
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Mitochondrial Caseinolytic Protease P: A Possible Novel Prognostic Marker and Therapeutic Target in Cancer. Int J Mol Sci 2021; 22:ijms22126228. [PMID: 34207660 PMCID: PMC8228031 DOI: 10.3390/ijms22126228] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/06/2021] [Accepted: 06/07/2021] [Indexed: 12/25/2022] Open
Abstract
Caseinolytic protease P (ClpP) is a mitochondrial serine protease. In mammalian cells, the heterodimerization of ClpP and its AAA+ ClpX chaperone results in a complex called ClpXP, which has a relevant role in protein homeostasis and in maintaining mitochondrial functionality through the degradation of mitochondrial misfolded or damaged proteins. Recent studies demonstrate that ClpP is upregulated in primary and metastatic human tumors, supports tumor cell proliferation, and its overexpression desensitizes cells to cisplatin. Interestingly, small modulators of ClpP activity, both activators and inhibitors, are able to impair oxidative phosphorylation in cancer cells and to induce apoptosis. This review provides an overview of the role of ClpP in regulating mitochondrial functionality, in supporting tumor cell proliferation and cisplatin resistance; finally, we discuss whether this protease could represent a new prognostic marker and therapeutic target for the treatment of cancer.
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28
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Weng H, Ma Y, Chen L, Cai G, Chen Z, Zhang S, Ye Q. A New Vision of Mitochondrial Unfolded Protein Response to the Sirtuin Family. Curr Neuropharmacol 2021; 18:613-623. [PMID: 31976838 PMCID: PMC7457425 DOI: 10.2174/1570159x18666200123165002] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 01/01/2020] [Accepted: 01/22/2020] [Indexed: 02/07/2023] Open
Abstract
Mitochondrial damage is involved in many pathophysiological processes, such as tumor development, metabolism, and neurodegenerative diseases. The mitochondrial unfolded protein response (mtUPR) is the first stress-protective response initiated by mitochondrial damage, and it repairs or clears misfolded proteins to alleviate this damage. Studies have confirmed that the sirtuin family is essential for the mitochondrial stress response; in particular, SIRT1, SIRT3, and SIRT7 participate in the mtUPR in different axes. This article summarizes the associations of sirtuins with the mtUPR as well as specific molecular targets related to the mtUPR in different disease models, which will provide new inspiration for studies on mitochondrial stress, mitochondrial function protection, and mitochondria-related diseases, such as neurodegenerative diseases.
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Affiliation(s)
- Huidan Weng
- Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan
Road, Fuzhou, Fujian, 350001, China,Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian, 350001, China,The 900th Hospital of Joint Logistic Support Force, PLA, Fuzhou, Fujian, China
| | - Yihong Ma
- Department of Neurology, Graduate School of Medical Sciences Kumamoto University, Kumamoto, Japan
| | - Lina Chen
- Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan
Road, Fuzhou, Fujian, 350001, China,Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian, 350001, China
| | - Guoen Cai
- Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan
Road, Fuzhou, Fujian, 350001, China,Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350001, China
| | - Zhiting Chen
- Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan
Road, Fuzhou, Fujian, 350001, China,Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350001, China
| | - Shaochuan Zhang
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Qinyong Ye
- Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan
Road, Fuzhou, Fujian, 350001, China,Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350001, China
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29
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Li TY, Sleiman MB, Li H, Gao AW, Mottis A, Bachmann AM, El Alam G, Li X, Goeminne LJE, Schoonjans K, Auwerx J. The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress. ACTA ACUST UNITED AC 2021; 1:165-178. [PMID: 33718883 PMCID: PMC7116894 DOI: 10.1038/s43587-020-00025-z] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Organisms respond to mitochondrial stress by activating multiple defense pathways including the mitochondrial unfolded protein response (UPRmt). However, how UPRmt regulators are orchestrated to transcriptionally activate stress responses remains largely unknown. Here we identified CBP-1, the worm ortholog of the mammalian acetyltransferases CBP/p300, as an essential regulator of the UPRmt, as well as mitochondrial stress-induced immune response, reduction of amyloid-β aggregation and lifespan extension in Caenorhabditis elegans. Mechanistically, CBP-1 acts downstream of histone demethylases, JMJD-1.2/JMJD-3.1, and upstream of UPRmt transcription factors including ATFS-1, to systematically induce a broad spectrum of UPRmt genes and execute multiple beneficial functions. In mouse and human populations, transcript levels of CBP/p300 positively correlate with UPRmt transcripts and longevity. Furthermore, CBP/p300 inhibition disrupts, while forced expression of p300 is sufficient to activate, the UPRmt in mammalian cells. These results highlight an evolutionarily conserved mechanism that determines mitochondrial stress response, and promotes health and longevity through CBP/p300.
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Affiliation(s)
- Terytty Yang Li
- Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Maroun Bou Sleiman
- Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Laboratory of Metabolic Signaling, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Hao Li
- Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Arwen W Gao
- Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Adrienne Mottis
- Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Alexis Maximilien Bachmann
- Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Gaby El Alam
- Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Xiaoxu Li
- Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Ludger J E Goeminne
- Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Kristina Schoonjans
- Laboratory of Metabolic Signaling, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Johan Auwerx
- Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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30
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FANCD2 modulates the mitochondrial stress response to prevent common fragile site instability. Commun Biol 2021; 4:127. [PMID: 33514811 PMCID: PMC7846573 DOI: 10.1038/s42003-021-01647-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 12/29/2020] [Indexed: 12/16/2022] Open
Abstract
Common fragile sites (CFSs) are genomic regions frequently involved in cancer-associated rearrangements. Most CFSs lie within large genes, and their instability involves transcription- and replication-dependent mechanisms. Here, we uncover a role for the mitochondrial stress response pathway in the regulation of CFS stability in human cells. We show that FANCD2, a master regulator of CFS stability, dampens the activation of the mitochondrial stress response and prevents mitochondrial dysfunction. Genetic or pharmacological activation of mitochondrial stress signaling induces CFS gene expression and concomitant relocalization to CFSs of FANCD2. FANCD2 attenuates CFS gene transcription and promotes CFS gene stability. Mechanistically, we demonstrate that the mitochondrial stress-dependent induction of CFS genes is mediated by ubiquitin-like protein 5 (UBL5), and that a UBL5-FANCD2 dependent axis regulates the mitochondrial UPR in human cells. We propose that FANCD2 coordinates nuclear and mitochondrial activities to prevent genome instability.
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31
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Abstract
Mounting evidence suggests a role for mitochondrial dysfunction in the pathogenesis of many diseases, including type 2 diabetes, aging, and ovarian failure. Because of the central role of mitochondria in energy production, heme biosynthesis, calcium buffering, steroidogenesis, and apoptosis signaling within cells, understanding the molecular mechanisms behind mitochondrial dysregulation and its potential implications in disease is critical. This review will take a journey through the past and summarize what is known about mitochondrial dysfunction in various disorders, focusing on metabolic alterations and reproductive abnormalities. Evidence is presented from studies in different human populations, and rodents with genetic manipulations of pathways known to affect mitochondrial function.
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Affiliation(s)
- Manasi Das
- VA San Diego Healthcare System, San Diego, California
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California
| | - Consuelo Sauceda
- VA San Diego Healthcare System, San Diego, California
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California
| | - Nicholas J G Webster
- VA San Diego Healthcare System, San Diego, California
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California
- Moores Cancer Center, University of California, San Diego, La Jolla, California
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32
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Mata-Cabana A, Pérez-Nieto C, Olmedo M. Nutritional control of postembryonic development progression and arrest in Caenorhabditis elegans. ADVANCES IN GENETICS 2020; 107:33-87. [PMID: 33641748 DOI: 10.1016/bs.adgen.2020.11.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Developmental programs are under strict genetic control that favors robustness of the process. In order to guarantee the same outcome in different environmental situations, development is modulated by input pathways, which inform about external conditions. In the nematode Caenorhabditis elegans, the process of postembryonic development involves a series of stereotypic cell divisions, the progression of which is controlled by the nutritional status of the animal. C. elegans can arrest development at different larval stages, leading to cell arrest of the relevant divisions of the stage. This means that studying the nutritional control of development in C. elegans we can learn about the mechanisms controlling cell division in an in vivo model. In this work, we reviewed the current knowledge about the nutrient sensing pathways that control the progression or arrest of development in response to nutrient availability, with a special focus on the arrest at the L1 stage.
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Affiliation(s)
- Alejandro Mata-Cabana
- Departamento de Genética, Facultad de Biología, Universidad de Sevilla, Avd. Reina Mercedes, Sevilla, Spain
| | - Carmen Pérez-Nieto
- Departamento de Genética, Facultad de Biología, Universidad de Sevilla, Avd. Reina Mercedes, Sevilla, Spain
| | - María Olmedo
- Departamento de Genética, Facultad de Biología, Universidad de Sevilla, Avd. Reina Mercedes, Sevilla, Spain.
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33
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Song Y, Zhou Y, Zhou X. The role of mitophagy in innate immune responses triggered by mitochondrial stress. Cell Commun Signal 2020; 18:186. [PMID: 33239048 PMCID: PMC7687798 DOI: 10.1186/s12964-020-00659-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 09/06/2020] [Indexed: 12/16/2022] Open
Abstract
Mitochondria are important cellular organelles involved in many different functions, from energy generation and fatty acid oxidation to cell death regulation and immune responses. Accumulating evidence indicates that mitochondrial stress acts as a key trigger of innate immune responses. Critically, the dysfunctional mitochondria can be selectively eliminated by mitophagy. The elimination of dysfunctional mitochondria may function as an effective way employed by mitophagy to keep the immune system in check. In addition, mitophagy can be utilized by pathogens for immune evasion. In this review, we summarize how mitochondrial stress triggers innate immune responses and the roles of mitophagy in innate immunity and in infection, as well as the molecular mechanisms of mitophagy. Video Abstract.
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Affiliation(s)
- Yinjuan Song
- Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China
| | - Yang Zhou
- College of Animal Science, Southwest University, Chongqing, 402460, China.,Immunology Research Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Xiangmei Zhou
- Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.
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34
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English J, Son JM, Cardamone MD, Lee C, Perissi V. Decoding the rosetta stone of mitonuclear communication. Pharmacol Res 2020; 161:105161. [PMID: 32846213 PMCID: PMC7755734 DOI: 10.1016/j.phrs.2020.105161] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/04/2020] [Accepted: 08/14/2020] [Indexed: 12/12/2022]
Abstract
Cellular homeostasis in eukaryotic cells requires synchronized coordination of multiple organelles. A key role in this stage is played by mitochondria, which have recently emerged as highly interconnected and multifunctional hubs that process and coordinate diverse cellular functions. Beyond producing ATP, mitochondria generate key metabolites and are central to apoptotic and metabolic signaling pathways. Because most mitochondrial proteins are encoded in the nuclear genome, the biogenesis of new mitochondria and the maintenance of mitochondrial functions and flexibility critically depend upon effective mitonuclear communication. This review addresses the complex network of signaling molecules and pathways allowing mitochondria-nuclear communication and coordinated regulation of their independent but interconnected genomes, and discusses the extent to which dynamic communication between the two organelles has evolved for mutual benefit and for the overall maintenance of cellular and organismal fitness.
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Affiliation(s)
- Justin English
- Department of Biochemistry, Boston University, Boston, MA, 02115, USA; Graduate Program in Biomolecular Pharmacology, Department of Pharmacology and Experimental Therapeutics, Boston University, Boston, MA, 02115, USA
| | - Jyung Mean Son
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
| | | | - Changhan Lee
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA; USC Norris Comprehensive Cancer Center, Los Angeles, CA, 90089, USA; Biomedical Sciences, Graduate School, Ajou University, Suwon, 16499, South Korea
| | - Valentina Perissi
- Department of Biochemistry, Boston University, Boston, MA, 02115, USA.
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35
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Nouri K, Feng Y, Schimmer AD. Mitochondrial ClpP serine protease-biological function and emerging target for cancer therapy. Cell Death Dis 2020; 11:841. [PMID: 33037181 PMCID: PMC7547079 DOI: 10.1038/s41419-020-03062-z] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 09/22/2020] [Accepted: 09/24/2020] [Indexed: 12/12/2022]
Abstract
Mitochondrial ClpP is a serine protease located in the mitochondrial matrix. This protease participates in mitochondrial protein quality control by degrading misfolded or damaged proteins, thus maintaining normal metabolic function. Mitochondrial ClpP is a stable heptamer ring with peptidase activity that forms a multimeric complex with the ATP-dependent unfoldase ClpX (ClpXP) leading to proteolytic activity. Emerging evidence demonstrates that ClpXP is over-expressed in hematologic malignancies and solid tumors and is necessary for the viability of a subset of tumors. In addition, both inhibition and hyperactivation of ClpXP leads to impaired respiratory chain activity and causes cell death in cancer cells. Therefore, targeting mitochondrial ClpXP could be a novel therapeutic strategy for the treatment of malignancy. Here, we review the structure and function of mitochondrial ClpXP as well as strategies to target this enzyme complex as a novel therapeutic approach for malignancy.
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Affiliation(s)
- Kazem Nouri
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Yue Feng
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Aaron D Schimmer
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
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36
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Zhou ZD, Tan EK. Oxidized nicotinamide adenine dinucleotide-dependent mitochondrial deacetylase sirtuin-3 as a potential therapeutic target of Parkinson's disease. Ageing Res Rev 2020; 62:101107. [PMID: 32535274 DOI: 10.1016/j.arr.2020.101107] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/18/2020] [Accepted: 06/05/2020] [Indexed: 12/11/2022]
Abstract
Mitochondrial impairment is associated with progressive dopamine (DA) neuron degeneration in Parkinson's disease (PD). Recent findings highlight that Sirtuin-3 (SIRT3), a mitochondrial protein, is an oxidized nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase and a key modulator in maintaining integrity and functions of mitochondria. SIRT3 plays vital roles in regulation of mitochondrial functions, including mitochondrial ATP generation and energy metabolism, anti-oxidant defense, and cell death and proliferation. SIRT3 can deacetylate the transcriptional factors and crosstalk with different signaling pathways to cooperatively modulate mitochondrial functions and regulate defensive mitochondrial quality control (QC) systems. Down-regulated NAD+ level and decreased SIRT3 activity are related to aging process and has been pathologically linked to PD pathogenesis. Further, SIRT3 can bind and deacetylate PTEN-induced kinase 1 (PINK1) and PD protein 2 E3 ubiquitin protein ligase (Parkin) to facilitate mitophagy. Leucine Rich Repeat Kinase 2 (LRRK2)-G2019S mutation in PD is linked to SIRT3 impairment. Furthermore, SIRT3 is inversely associated with α-synuclein aggregation and DA neuron degeneration in PD. SIRT3 chemical activators and NAD+ precursors can up-regulate SIRT3 activity to protect against DA neuron degeneration in PD models. Taken together, SIRT3 is a promising PD therapeutic target and studies of SIRT3 functional modulators with neuroprotective capability will be of clinical interest.
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Affiliation(s)
- Zhi Dong Zhou
- National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore; Duke-NUS Graduate Medical School, 8 College Road, 169857, Singapore.
| | - Eng King Tan
- National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433, Singapore; Department of Neurology, Singapore General Hospital, Outram Road, 169608, Singapore; Duke-NUS Graduate Medical School, 8 College Road, 169857, Singapore.
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37
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Bornstein R, Gonzalez B, Johnson SC. Mitochondrial pathways in human health and aging. Mitochondrion 2020; 54:72-84. [PMID: 32738358 PMCID: PMC7508824 DOI: 10.1016/j.mito.2020.07.007] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 07/20/2020] [Accepted: 07/27/2020] [Indexed: 12/27/2022]
Abstract
Mitochondria are eukaryotic organelles known best for their roles in energy production and metabolism. While often thought of as simply the 'powerhouse of the cell,' these organelles participate in a variety of critical cellular processes including reactive oxygen species (ROS) production, regulation of programmed cell death, modulation of inter- and intracellular nutrient signaling pathways, and maintenance of cellular proteostasis. Disrupted mitochondrial function is a hallmark of eukaryotic aging, and mitochondrial dysfunction has been reported to play a role in many aging-related diseases. While mitochondria are major players in human diseases, significant questions remain regarding their precise mechanistic role. In this review, we detail mechanisms by which mitochondrial dysfunction participate in disease and aging based on findings from model organisms and human genetics studies.
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Affiliation(s)
| | - Brenda Gonzalez
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Simon C Johnson
- Department of Neurology, University of Washington, Seattle, WA, USA; Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
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38
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Matrix Metalloproteinase-11 Promotes Early Mouse Mammary Gland Tumor Growth through Metabolic Reprogramming and Increased IGF1/AKT/FoxO1 Signaling Pathway, Enhanced ER Stress and Alteration in Mitochondrial UPR. Cancers (Basel) 2020; 12:cancers12092357. [PMID: 32825455 PMCID: PMC7565046 DOI: 10.3390/cancers12092357] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/17/2020] [Accepted: 08/17/2020] [Indexed: 12/21/2022] Open
Abstract
Matrix metalloproteinase 11 (MMP11) is an extracellular proteolytic enzyme belonging to the matrix metalloproteinase (MMP11) family. These proteases are involved in extracellular matrix (ECM) remodeling and activation of latent factors. MMP11 is a negative regulator of adipose tissue development and controls energy metabolism in vivo. In cancer, MMP11 expression is associated with poorer survival, and preclinical studies in mice showed that MMP11 accelerates tumor growth. How the metabolic role of MMP11 contributes to cancer development is poorly understood. To address this issue, we developed a series of preclinical mouse mammary gland tumor models by genetic engineering. Tumor growth was studied in mice either deficient (Loss of Function-LOF) or overexpressing MMP11 (Gain of Function-GOF) crossed with a transgenic model of breast cancer induced by the polyoma middle T antigen (PyMT) driven by the murine mammary tumor virus promoter (MMTV) (MMTV-PyMT). Both GOF and LOF models support roles for MMP11, favoring early tumor growth by increasing proliferation and reducing apoptosis. Of interest, MMP11 promotes Insulin-like Growth Factor-1 (IGF1)/protein kinase B (AKT)/Forkhead box protein O1 (FoxO1) signaling and is associated with a metabolic switch in the tumor, activation of the endoplasmic reticulum stress response, and an alteration in the mitochondrial unfolded protein response with decreased proteasome activity. In addition, high resonance magic angle spinning (HRMAS) metabolomics analysis of tumors from both models established a metabolic signature that favors tumorigenesis when MMP11 is overexpressed. These data support the idea that MMP11 contributes to an adaptive metabolic response, named metabolic flexibility, promoting cancer growth.
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39
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Chen FM, Huang LJ, Ou-Yang F, Kan JY, Kao LC, Hou MF. Activation of mitochondrial unfolded protein response is associated with Her2-overexpression breast cancer. Breast Cancer Res Treat 2020; 183:61-70. [PMID: 32601970 DOI: 10.1007/s10549-020-05729-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 06/03/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE Mitochondrial unfolding protein are abundant in breast cancer cells, but the mechanism by which breast cancer cells resist apoptosis is still not fully elucidated. In this study, we explored the role of mitochondrial unfolded protein response (mtUPR)-related proteins in four types of breast cancer tissues. METHODS Mitochondrial fractions were taken from four breast cancer tissues (luminal A, luminal B, Her2 -overexpression, and TNBC) and the expression of mitochondrial polyubiquitinated proteins was observed by western blot and ELISA. In addition, the expression of hsp10, hsp60, and clpp in mitochondria was observed by western blot in breast cancer tissues and adjacent tissues, and confirmed by ELISA. The expression levels of hsp10 and hsp60 were correlated with clinicopathological parameters in 114 breast cancer patients. RESULTS We found an increase in the performance of mitochondrial polyubiquitinated proteins in breast cancer tissues of luminal A, luminal B, Her2-overexpression, and TNBC. The mitochondrial hsp10, hsp60, and clpp are abundantly expressed in breast cancer tissues rather than adjacent noncancerous tissues. The expression levels of mitochondrial hsp10 and hsp60 were highest in histological grade 3 breast cancer tissues. Additionally, mitochondria with high hsp60 expression were more present in Her2-positive tumors. CONCLUSIONS We observed that mtUPR was specifically activated in breast cancer tissues but inactivated in normal mammary tissue. MtUPR had also exhibited a particular increase in Her2-overexpression tumors but not in ER- or PR-positive tumors. Taken together, we suggested that mtUPR may act as a potential candidate for developing novel Her2-overexpression breast cancer therapy.
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Affiliation(s)
- Fang-Ming Chen
- Division of Breast Surgery, Department of Surgery, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung, 807, Taiwan, ROC.,Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, No. 68, Zhonghua 3rd Rd., Qianjin Dist., Kaohsiung, 801, Taiwan, ROC.,Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, No. 100, Tzyou 1st Road, Kaohsiung, 807, Taiwan, ROC.,Drug Development and Value Creation Research Center, Kaohsiung Medical University, No. 100, Tzyou 1st Road, Kaohsiung, 807, Taiwan, ROC
| | - Li-Ju Huang
- Center of Teaching and Research, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Fu Ou-Yang
- Division of Breast Surgery, Department of Surgery, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung, 807, Taiwan, ROC.,Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, No. 68, Zhonghua 3rd Rd., Qianjin Dist., Kaohsiung, 801, Taiwan, ROC
| | - Jung-Yu Kan
- Division of Breast Surgery, Department of Surgery, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung, 807, Taiwan, ROC.,Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, No. 68, Zhonghua 3rd Rd., Qianjin Dist., Kaohsiung, 801, Taiwan, ROC
| | - Li-Chun Kao
- Division of Breast Surgery, Department of Surgery, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung, 807, Taiwan, ROC.,Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, No. 68, Zhonghua 3rd Rd., Qianjin Dist., Kaohsiung, 801, Taiwan, ROC
| | - Ming-Feng Hou
- Division of Breast Surgery, Department of Surgery, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung, 807, Taiwan, ROC. .,Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, No. 68, Zhonghua 3rd Rd., Qianjin Dist., Kaohsiung, 801, Taiwan, ROC. .,Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, No. 100, Tzyou 1st Road, Kaohsiung, 807, Taiwan, ROC. .,Drug Development and Value Creation Research Center, Kaohsiung Medical University, No. 100, Tzyou 1st Road, Kaohsiung, 807, Taiwan, ROC.
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40
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Cai Y, Shen H, Weng H, Wang Y, Cai G, Chen X, Ye Q. Overexpression of PGC-1α influences the mitochondrial unfolded protein response (mtUPR) induced by MPP + in human SH-SY5Y neuroblastoma cells. Sci Rep 2020; 10:10444. [PMID: 32591623 PMCID: PMC7320005 DOI: 10.1038/s41598-020-67229-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 06/03/2020] [Indexed: 12/13/2022] Open
Abstract
Parkinson’s disease (PD) is a common dyskinesia disease, the mitochondrial unfolded protein response (mtUPR) may be directly or indirectly involved in the occurrence and development of PD, although the exact mechanism is unclear. We established a dopaminergic neuronal-like cell model of PD, by overexpression of PGC-1α to detect evaluate the expression of proteases and molecular chaperones of involved in the mtUPR, as well as the expression of PGC-1α and LRPPRC, illustrated the distribution of LRPPRC. Remarkably, the mtUPR activation reached maximal at 24 h after MPP+ treatment in SH-SY5Y cells, which the protein and transcription levels of the proteases and molecular chaperones reached maximal. The proteases and molecular chaperones were significantly increased when overexpressed PGC-1α, which indicated that PGC-1α overexpression activated the mtUPR, and PGC-1α had a protective effect on SH-SY5Y cells. The expression levels of PGC-1α and LRPPRC were significantly improved in the PGC-1α overexpression groups. LRPPRC was markedly reduced in the nucleus, suggesting that PGC-1α overexpression may play a protective role to the mitochondria through LRPPRC. Our finding indicates that overexpression of PGC-1α may activate mtUPR, reducing the oxidative stress injury induced by MPP+ through LRPPRC signaling, thus maintain mitochondrial homeostasis.
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Affiliation(s)
- Yousheng Cai
- Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian, 350001, China.,Department of Neurology, Zhangzhou Affiliated Hospital of Fujian Medical University, 59 Shengli Road, Zhangzhou, 363000, China
| | - Hui Shen
- Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian, 350001, China
| | - Huidan Weng
- Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian, 350001, China.,Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China
| | - Yingqing Wang
- Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian, 350001, China
| | - Guoen Cai
- Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian, 350001, China
| | - Xiaochun Chen
- Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian, 350001, China.,Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China
| | - Qinyong Ye
- Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian, 350001, China. .,Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.
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41
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Yan X, Wang B, Hu Y, Wang S, Zhang X. Abnormal Mitochondrial Quality Control in Neurodegenerative Diseases. Front Cell Neurosci 2020; 14:138. [PMID: 32655368 PMCID: PMC7324542 DOI: 10.3389/fncel.2020.00138] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 04/22/2020] [Indexed: 12/12/2022] Open
Abstract
Neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis, are characterized by a progressive loss of selective neuron subtypes in the central nervous system (CNS). Although various factors account for the initiation and development of these diseases, accumulating evidence shows that impaired mitochondrial function is a prominent and common mechanism. Mitochondria play a critical role in neurons and are involved in energy production, cellular metabolism regulation, intracellular calcium homeostasis, immune responses, and cell fate. Thus, cells in the CNS heavily rely on mitochondrial integrity. Many aspects of mitochondrial dysfunction are manifested in neurodegenerative diseases, including aberrant mitochondrial quality control (mitoQC), mitochondrial-driven inflammation, and bioenergetic defects. Herein, we briefly summarize the molecular basis of mitoQC, including mitochondrial proteostasis, biogenesis, dynamics, and organelle degradation. We also focus on the research, to date, regarding aberrant mitoQC and mitochondrial-driven inflammation in several common neurodegenerative diseases. In addition, we outline novel therapeutic strategies that target aberrant mitoQC in neurodegenerative diseases.
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Affiliation(s)
- Xu Yan
- The VIP Department, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Biyao Wang
- The VIP Department, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Yue Hu
- The VIP Department, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Sijian Wang
- Center of Implant Dentistry, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Xinwen Zhang
- Center of Implant Dentistry, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
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42
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Yan X, Wang B, Hu Y, Wang S, Zhang X. Abnormal Mitochondrial Quality Control in Neurodegenerative Diseases. Front Cell Neurosci 2020; 14:138. [PMID: 32655368 DOI: 10.3389/fncel.2020.00138/xml/nlm] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 04/22/2020] [Indexed: 05/25/2023] Open
Abstract
Neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis, are characterized by a progressive loss of selective neuron subtypes in the central nervous system (CNS). Although various factors account for the initiation and development of these diseases, accumulating evidence shows that impaired mitochondrial function is a prominent and common mechanism. Mitochondria play a critical role in neurons and are involved in energy production, cellular metabolism regulation, intracellular calcium homeostasis, immune responses, and cell fate. Thus, cells in the CNS heavily rely on mitochondrial integrity. Many aspects of mitochondrial dysfunction are manifested in neurodegenerative diseases, including aberrant mitochondrial quality control (mitoQC), mitochondrial-driven inflammation, and bioenergetic defects. Herein, we briefly summarize the molecular basis of mitoQC, including mitochondrial proteostasis, biogenesis, dynamics, and organelle degradation. We also focus on the research, to date, regarding aberrant mitoQC and mitochondrial-driven inflammation in several common neurodegenerative diseases. In addition, we outline novel therapeutic strategies that target aberrant mitoQC in neurodegenerative diseases.
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Affiliation(s)
- Xu Yan
- The VIP Department, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Biyao Wang
- The VIP Department, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Yue Hu
- The VIP Department, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Sijian Wang
- Center of Implant Dentistry, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Xinwen Zhang
- Center of Implant Dentistry, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
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43
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Shen G, Liu W, Xu L, Wang LL. Mitochondrial Unfolded Protein Response and Its Roles in Stem Cells. Stem Cells Dev 2020; 29:627-637. [PMID: 32070227 DOI: 10.1089/scd.2019.0278] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
- Gerong Shen
- Department of Basic Medicine Sciences, Zhejiang University School of Medicine, Hangzhou, China
- Department of Orthopaedics of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Liu
- Department of Prosthetics, Stomatology Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lvwan Xu
- Department of Basic Medicine Sciences, Zhejiang University School of Medicine, Hangzhou, China
- Department of Orthopaedics of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lin-lin Wang
- Department of Basic Medicine Sciences, Zhejiang University School of Medicine, Hangzhou, China
- Department of Orthopaedics of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
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44
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Vannini N, Campos V, Girotra M, Trachsel V, Rojas-Sutterlin S, Tratwal J, Ragusa S, Stefanidis E, Ryu D, Rainer PY, Nikitin G, Giger S, Li TY, Semilietof A, Oggier A, Yersin Y, Tauzin L, Pirinen E, Cheng WC, Ratajczak J, Canto C, Ehrbar M, Sizzano F, Petrova TV, Vanhecke D, Zhang L, Romero P, Nahimana A, Cherix S, Duchosal MA, Ho PC, Deplancke B, Coukos G, Auwerx J, Lutolf MP, Naveiras O. The NAD-Booster Nicotinamide Riboside Potently Stimulates Hematopoiesis through Increased Mitochondrial Clearance. Cell Stem Cell 2020; 24:405-418.e7. [PMID: 30849366 DOI: 10.1016/j.stem.2019.02.012] [Citation(s) in RCA: 153] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 12/18/2018] [Accepted: 02/13/2019] [Indexed: 12/22/2022]
Abstract
It has been recently shown that increased oxidative phosphorylation, as reflected by increased mitochondrial activity, together with impairment of the mitochondrial stress response, can severely compromise hematopoietic stem cell (HSC) regeneration. Here we show that the NAD+-boosting agent nicotinamide riboside (NR) reduces mitochondrial activity within HSCs through increased mitochondrial clearance, leading to increased asymmetric HSC divisions. NR dietary supplementation results in a significantly enlarged pool of progenitors, without concurrent HSC exhaustion, improves survival by 80%, and accelerates blood recovery after murine lethal irradiation and limiting-HSC transplantation. In immune-deficient mice, NR increased the production of human leucocytes from hCD34+ progenitors. Our work demonstrates for the first time a positive effect of NAD+-boosting strategies on the most primitive blood stem cells, establishing a link between HSC mitochondrial stress, mitophagy, and stem-cell fate decision, and unveiling the potential of NR to improve recovery of patients suffering from hematological failure including post chemo- and radiotherapy.
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Affiliation(s)
- Nicola Vannini
- Laboratory of Regenerative Hematopoiesis, Swiss Institute for Experimental Cancer Research (ISREC) & Institute of Bioengineering (IBI), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges 1066, Switzerland.
| | - Vasco Campos
- Laboratory of Regenerative Hematopoiesis, Swiss Institute for Experimental Cancer Research (ISREC) & Institute of Bioengineering (IBI), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Mukul Girotra
- Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges 1066, Switzerland; Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Vincent Trachsel
- Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Shanti Rojas-Sutterlin
- Laboratory of Regenerative Hematopoiesis, Swiss Institute for Experimental Cancer Research (ISREC) & Institute of Bioengineering (IBI), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Josefine Tratwal
- Laboratory of Regenerative Hematopoiesis, Swiss Institute for Experimental Cancer Research (ISREC) & Institute of Bioengineering (IBI), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Simone Ragusa
- Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges 1066, Switzerland
| | - Evangelos Stefanidis
- Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges 1066, Switzerland; Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
| | - Dongryeol Ryu
- Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Pernille Y Rainer
- Laboratory of System Biology and Genetics, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Gena Nikitin
- Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Sonja Giger
- Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Terytty Y Li
- Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Aikaterini Semilietof
- Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges 1066, Switzerland; Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
| | - Aurelien Oggier
- Laboratory of Regenerative Hematopoiesis, Swiss Institute for Experimental Cancer Research (ISREC) & Institute of Bioengineering (IBI), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Yannick Yersin
- Laboratory of Regenerative Hematopoiesis, Swiss Institute for Experimental Cancer Research (ISREC) & Institute of Bioengineering (IBI), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Loïc Tauzin
- Flow Cytometry Platform, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Eija Pirinen
- Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Wan-Chen Cheng
- Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges 1066, Switzerland
| | - Joanna Ratajczak
- Nestlé Research, EPFL Innovation Park, 1015 Lausanne, Switzerland
| | - Carles Canto
- Nestlé Research, EPFL Innovation Park, 1015 Lausanne, Switzerland; School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Martin Ehrbar
- Department of Obstetrics, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Federico Sizzano
- Nestlé Research, EPFL Innovation Park, 1015 Lausanne, Switzerland
| | - Tatiana V Petrova
- Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges 1066, Switzerland; Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences. Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
| | - Dominique Vanhecke
- Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges 1066, Switzerland
| | - Lianjun Zhang
- Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges 1066, Switzerland
| | - Pedro Romero
- Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges 1066, Switzerland
| | - Aimable Nahimana
- Service and Central Laboratory of Hematology, Departments of Oncology and of Laboratories, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - Stephane Cherix
- Service d'orthopédie et de traumatologie, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - Michel A Duchosal
- Service and Central Laboratory of Hematology, Departments of Oncology and of Laboratories, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - Ping-Chih Ho
- Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges 1066, Switzerland
| | - Bart Deplancke
- Laboratory of System Biology and Genetics, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - George Coukos
- Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Epalinges 1066, Switzerland
| | - Johan Auwerx
- Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Matthias P Lutolf
- Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Institute of Chemical Sciences and Engineering, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Olaia Naveiras
- Laboratory of Regenerative Hematopoiesis, Swiss Institute for Experimental Cancer Research (ISREC) & Institute of Bioengineering (IBI), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Service and Central Laboratory of Hematology, Departments of Oncology and of Laboratories, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
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45
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Li X, Zeng X, Xu Y, Wang B, Zhao Y, Lai X, Qian P, Huang H. Mechanisms and rejuvenation strategies for aged hematopoietic stem cells. J Hematol Oncol 2020; 13:31. [PMID: 32252797 PMCID: PMC7137344 DOI: 10.1186/s13045-020-00864-8] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 03/27/2020] [Indexed: 12/18/2022] Open
Abstract
Hematopoietic stem cell (HSC) aging, which is accompanied by reduced self-renewal ability, impaired homing, myeloid-biased differentiation, and other defects in hematopoietic reconstitution function, is a hot topic in stem cell research. Although the number of HSCs increases with age in both mice and humans, the increase cannot compensate for the defects of aged HSCs. Many studies have been performed from various perspectives to illustrate the potential mechanisms of HSC aging; however, the detailed molecular mechanisms remain unclear, blocking further exploration of aged HSC rejuvenation. To determine how aged HSC defects occur, we provide an overview of differences in the hallmarks, signaling pathways, and epigenetics of young and aged HSCs as well as of the bone marrow niche wherein HSCs reside. Notably, we summarize the very recent studies which dissect HSC aging at the single-cell level. Furthermore, we review the promising strategies for rejuvenating aged HSC functions. Considering that the incidence of many hematological malignancies is strongly associated with age, our HSC aging review delineates the association between functional changes and molecular mechanisms and may have significant clinical relevance.
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Affiliation(s)
- Xia Li
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, People's Republic of China
| | - Xiangjun Zeng
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, People's Republic of China
| | - Yulin Xu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, People's Republic of China
| | - Binsheng Wang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, People's Republic of China
| | - Yanmin Zhao
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, People's Republic of China
| | - Xiaoyu Lai
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, People's Republic of China
| | - Pengxu Qian
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, People's Republic of China
| | - He Huang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China. .,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China. .,Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, People's Republic of China.
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46
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Molenaars M, Janssens GE, Williams EG, Jongejan A, Lan J, Rabot S, Joly F, Moerland PD, Schomakers BV, Lezzerini M, Liu YJ, McCormick MA, Kennedy BK, van Weeghel M, van Kampen AHC, Aebersold R, MacInnes AW, Houtkooper RH. A Conserved Mito-Cytosolic Translational Balance Links Two Longevity Pathways. Cell Metab 2020; 31:549-563.e7. [PMID: 32084377 PMCID: PMC7214782 DOI: 10.1016/j.cmet.2020.01.011] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 08/22/2019] [Accepted: 01/22/2020] [Indexed: 12/13/2022]
Abstract
Slowing down translation in either the cytosol or the mitochondria is a conserved longevity mechanism. Here, we found a non-interventional natural correlation of mitochondrial and cytosolic ribosomal proteins (RPs) in mouse population genetics, suggesting a translational balance. Inhibiting mitochondrial translation in C. elegans through mrps-5 RNAi repressed cytosolic translation. Transcriptomics integrated with proteomics revealed that this inhibition specifically reduced translational efficiency of mRNAs required in growth pathways while increasing stress response mRNAs. The repression of cytosolic translation and extension of lifespan from mrps-5 RNAi were dependent on atf-5/ATF4 and independent from metabolic phenotypes. We found the translational balance to be conserved in mammalian cells upon inhibiting mitochondrial translation pharmacologically with doxycycline. Lastly, extending this in vivo, doxycycline repressed cytosolic translation in the livers of germ-free mice. These data demonstrate that inhibiting mitochondrial translation initiates an atf-5/ATF4-dependent cascade leading to coordinated repression of cytosolic translation, which could be targeted to promote longevity.
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Affiliation(s)
- Marte Molenaars
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
| | - Georges E Janssens
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
| | - Evan G Williams
- Institute of Molecular Systems Biology, ETH Zurich, Zürich, Switzerland
| | - Aldo Jongejan
- Bioinformatics Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Jiayi Lan
- Institute of Molecular Systems Biology, ETH Zurich, Zürich, Switzerland
| | - Sylvie Rabot
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Fatima Joly
- Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Perry D Moerland
- Bioinformatics Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Bauke V Schomakers
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands; Core Facility Metabolomics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Marco Lezzerini
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
| | - Yasmine J Liu
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
| | - Mark A McCormick
- Department of Biochemistry and Molecular Biology, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA; Autophagy, Inflammation, and Metabolism Center of Biological Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Brian K Kennedy
- Buck Institute for Research on Aging, Novato, CA, USA; Departments of Biochemistry and Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Michel van Weeghel
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands; Core Facility Metabolomics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Antoine H C van Kampen
- Bioinformatics Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Ruedi Aebersold
- Institute of Molecular Systems Biology, ETH Zurich, Zürich, Switzerland; Faculty of Science, University of Zürich, Switzerland
| | - Alyson W MacInnes
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
| | - Riekelt H Houtkooper
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands.
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47
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Zhang Y, Oliveira AN, Hood DA. The intersection of exercise and aging on mitochondrial protein quality control. Exp Gerontol 2020; 131:110824. [PMID: 31911185 DOI: 10.1016/j.exger.2019.110824] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 12/13/2019] [Accepted: 12/31/2019] [Indexed: 12/23/2022]
Abstract
Skeletal muscle quality and quantity are negatively impacted with age. Part of this decline in function can be attributed to alterations in mitochondrial turnover, and in the mechanisms that regulate mitochondrial homeostasis. Protein quality control within the mitochondria relies on a number of interconnected processes, namely the mitochondrial unfolded protein response (UPRmt), protein import and mitophagy. In particular, the post-transcriptional regulation of protein import into the organelle has generated considerable recent interest in view of its dynamic versatility. The capacity for import can be increased by chronic exercise, and diminished by muscle disuse, and defects in the import pathway can be rescued by exercise. Within mitochondria, the unfolded protein response (UPR) is activated if protein import is altered, or if protein misfolding takes place. This UPR generates retrograde signaling to the nucleus to activate compensatory gene expression and protein synthesis. Mitophagy is also elevated with age, contributing to the lower mitochondrial content in aging muscle. However, mitophagy is amenable to exercise adaptations, as it is activated with each exercise bout, presumably to mediate mitochondrial quality control. However, this response is attenuated in older subjects. Although not yet completely elucidated, numerous molecular processes involved in mitochondrial biogenesis and turnover are affected with age. The contrasting and often opposite consequences of exercise and age suggest that exercise can serve as non-pharmacological "mitochondrial medicine" for aging muscle to ameliorate mitochondrial content and function, via pathways that implicate organelle protein quality control mechanisms.
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Affiliation(s)
- Yuan Zhang
- School of Sports and Health, Nanjing Sport Institute, Nanjing, Jiangsu, China
| | - Ashley N Oliveira
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario M3J 1P3, Canada
| | - David A Hood
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario M3J 1P3, Canada.
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Morris G, Puri BK, Walker AJ, Berk M, Walder K, Bortolasci CC, Marx W, Carvalho AF, Maes M. The compensatory antioxidant response system with a focus on neuroprogressive disorders. Prog Neuropsychopharmacol Biol Psychiatry 2019; 95:109708. [PMID: 31351160 DOI: 10.1016/j.pnpbp.2019.109708] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 07/16/2019] [Accepted: 07/22/2019] [Indexed: 02/07/2023]
Abstract
Major antioxidant responses to increased levels of inflammatory, oxidative and nitrosative stress (ONS) are detailed. In response to increasing levels of nitric oxide, S-nitrosylation of cysteine thiol groups leads to post-transcriptional modification of many cellular proteins and thereby regulates their activity and allows cellular adaptation to increased levels of ONS. S-nitrosylation inhibits the function of nuclear factor kappa-light-chain-enhancer of activated B cells, toll-like receptor-mediated signalling and the activity of several mitogen-activated protein kinases, while activating nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2 or NFE2L2); in turn, the redox-regulated activation of Nrf2 leads to increased levels and/or activity of key enzymes and transporter systems involved in the glutathione system. The Nrf2/Kelch-like ECH-associated protein-1 axis is associated with upregulation of NAD(P)H:quinone oxidoreductase 1, which in turn has anti-inflammatory effects. Increased Nrf2 transcriptional activity also leads to activation of haem oxygenase-1, which is associated with upregulation of bilirubin, biliverdin and biliverdin reductase as well as increased carbon monoxide signalling, anti-inflammatory and antioxidant activity. Associated transcriptional responses, which may be mediated by retrograde signalling owing to elevated hydrogen peroxide, include the unfolded protein response (UPR), mitohormesis and the mitochondrial UPR; the UPR also results from increasing levels of mitochondrial and cytosolic reactive oxygen species and reactive nitrogen species leading to nitrosylation, glutathionylation, oxidation and nitration of crucial cysteine and tyrosine causing protein misfolding and the development of endoplasmic reticulum stress. It is shown how these mechanisms co-operate in forming a co-ordinated rapid and prolonged compensatory antioxidant response system.
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Affiliation(s)
- Gerwyn Morris
- IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Basant K Puri
- Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom
| | - Adam J Walker
- IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Michael Berk
- IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, The Department of Psychiatry, The Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia
| | - Ken Walder
- CMMR Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Chiara C Bortolasci
- CMMR Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Wolfgang Marx
- IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Andre F Carvalho
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada.
| | - Michael Maes
- IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
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Bozi LHM, Campos JC, Zambelli VO, Ferreira ND, Ferreira JCB. Mitochondrially-targeted treatment strategies. Mol Aspects Med 2019; 71:100836. [PMID: 31866004 DOI: 10.1016/j.mam.2019.100836] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/11/2019] [Accepted: 12/13/2019] [Indexed: 12/13/2022]
Abstract
Disruption of mitochondrial function is a common feature of inherited mitochondrial diseases (mitochondriopathies) and many other infectious and non-infectious diseases including viral, bacterial and protozoan infections, inflammatory and chronic pain, neurodegeneration, diabetes, obesity and cardiovascular diseases. Mitochondria therefore become an attractive target for developing new therapies. In this review we describe critical mechanisms involved in the maintenance of mitochondrial functionality and discuss strategies used to identify and validate mitochondrial targets in different diseases. We also highlight the most recent preclinical and clinical findings using molecules targeting mitochondrial bioenergetics, morphology, number, content and detoxification systems in common pathologies.
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Affiliation(s)
- Luiz H M Bozi
- Institute of Biomedical Sciences, University of Sao Paulo, Brazil
| | - Juliane C Campos
- Institute of Biomedical Sciences, University of Sao Paulo, Brazil
| | | | | | - Julio C B Ferreira
- Institute of Biomedical Sciences, University of Sao Paulo, Brazil; Department of Chemical and Systems Biology, School of Medicine, Stanford University, USA.
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50
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Abstract
The mammalian kidney relies on abundant mitochondria in the renal tubule to generate sufficient ATP to provide the energy required for constant reclamation of solutes from crude blood filtrate. The highly metabolically active cells of the renal tubule also pair their energetic needs to the regulation of diverse cellular processes, including energy generation, antioxidant responses, autophagy and mitochondrial quality control. Nicotinamide adenine dinucleotide (NAD+) is essential not only for the harvesting of energy from substrates but also for an array of regulatory reactions that determine cellular health. In acute kidney injury (AKI), substantial decreases in the levels of NAD+ impair energy generation and, ultimately, the core kidney function of selective solute transport. Conversely, augmentation of NAD+ may protect the kidney tubule against diverse acute stressors. For example, NAD+ augmentation can ameliorate experimental AKI triggered by ischaemia–reperfusion, toxic injury and systemic inflammation. NAD+-dependent maintenance of renal tubular metabolic health may also attenuate long-term profibrotic responses that could lead to chronic kidney disease. Further understanding of the genetic, environmental and nutritional factors that influence NAD+ biosynthesis and renal resilience may lead to novel approaches for the prevention and treatment of kidney disease. Here, the authors discuss evidence for a role of NAD+ imbalance in the pathogenesis of acute kidney injury (AKI) and chronic kidney disease (CKD). They suggest that disruption of NAD+ metabolism may contribute to mechanistic links among AKI, CKD and ageing.
NAD+ has critical roles in the generation of ATP from fuel substrates and as a substrate for important enzymes that regulate cellular health and stress responses. The renal tubule is highly metabolically active and requires a constant supply of ATP to provide the energy required to pump solutes across unfavourable gradients. Experimental acute kidney injury (AKI) induced by various insults rapidly leads to a decrease in NAD+ levels that probably results from a combination of reduced NAD+ biosynthesis and increased NAD+ consumption. Renal NAD+ levels can be augmented using vitamin B3 analogues and related nutritional precursors. NAD+ augmentation can prevent and/or treat various aetiologies of experimental AKI and might also attenuate long-term profibrotic responses following AKI, suggesting a potential role in the treatment of chronic kidney disease.
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