|
1
|
Jiang H, Ye J. The Warburg effect: The hacked mitochondrial-nuclear communication in cancer. Semin Cancer Biol 2025; 112:93-111. [PMID: 40147702 DOI: 10.1016/j.semcancer.2025.03.006] [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: 07/31/2024] [Revised: 02/23/2025] [Accepted: 03/17/2025] [Indexed: 03/29/2025]
Abstract
Mitochondrial-nuclear communication is vital for maintaining cellular homeostasis. This communication begins with mitochondria sensing environmental cues and transmitting signals to the nucleus through the retrograde cascade, involving metabolic signals such as substrates for epigenetic modifications, ATP and AMP levels, calcium flux, etc. These signals inform the nucleus about the cell's metabolic state, remodel epigenome and regulate gene expression, and modulate mitochondrial function and dynamics through the anterograde feedback cascade to control cell fate and physiology. Disruption of this communication can lead to cellular dysfunction and disease progression, particularly in cancer. The Warburg effect is the metabolic hallmark of cancer, characterized by disruption of mitochondrial respiration and increased lactate generation from glycolysis. This metabolic reprogramming rewires retrograde signaling, leading to epigenetic changes and dedifferentiation, further reprogramming mitochondrial function and promoting carcinogenesis. Understanding these processes and their link to tumorigenesis is crucial for uncovering tumorigenesis mechanisms. Therapeutic strategies targeting these disrupted pathways, including metabolic and epigenetic components, provide promising avenues for cancer treatment.
Collapse
Affiliation(s)
- Haowen Jiang
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Jiangbin Ye
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
| |
Collapse
|
|
2
|
McGill Percy KC, Liu Z, Qi X. Mitochondrial dysfunction in Alzheimer's disease: Guiding the path to targeted therapies. Neurotherapeutics 2025; 22:e00525. [PMID: 39827052 PMCID: PMC12047401 DOI: 10.1016/j.neurot.2025.e00525] [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: 08/31/2024] [Revised: 01/07/2025] [Accepted: 01/07/2025] [Indexed: 01/22/2025] Open
Abstract
Alzheimer's disease (AD) is characterized by progressive neurodegeneration, marked by the accumulation of amyloid-β (Aβ) plaques and tau tangles. Emerging evidence suggests that mitochondrial dysfunction plays a pivotal role in AD pathogenesis, driven by impairments in mitochondrial quality control (MQC) mechanisms. MQC is crucial for maintaining mitochondrial integrity through processes such as proteostasis, mitochondrial dynamics, mitophagy, and precise communication with other subcellular organelles. In AD, disruptions in these processes lead to bioenergetic failure, gene dysregulation, the accumulation of damaged mitochondria, neuroinflammation, and lipid homeostasis impairment, further exacerbating neurodegeneration. This review elucidates the molecular pathways involved in MQC and their pathological relevance in AD, highlighting recent discoveries related to mitochondrial mechanisms underlying neurodegeneration. Furthermore, we explore potential therapeutic strategies targeting mitochondrial dysfunction, including gene therapy and pharmacological interventions, offering new avenues for slowing AD progression. The complex interplay between mitochondrial health and neurodegeneration underscores the need for innovative approaches to restore mitochondrial function and mitigate the onset and progression of AD.
Collapse
Affiliation(s)
- Kyle C McGill Percy
- Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Zunren Liu
- Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Xin Qi
- Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Center for Mitochondrial Research and Therapeutics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
| |
Collapse
|
|
3
|
Lee J, Woo H, Kang H, Park YK, Lee JY. Nicotinamide riboside targets mitochondrial unfolded protein response to reduce alcohol-induced damage in Kupffer cells. J Pathol 2025; 265:110-122. [PMID: 39624887 DOI: 10.1002/path.6372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 09/15/2024] [Accepted: 10/23/2024] [Indexed: 12/14/2024]
Abstract
The pathogenesis of alcohol-related liver disease (ALD) is closely linked to mitochondrial dysfunction and impaired cellular energy metabolism. In this study, we explored how ethanol triggers inflammation, oxidative stress, and mitochondrial dysfunction in Kupffer cells, i.e.hepatic resident macrophages, primarily focusing on the mitochondrial unfolded protein response (UPRmt) using immortalized mouse Kupffer cells (ImKCs) and mouse primary KCs. The UPRmt is a cellular defense mechanism activated in response to the perturbation of mitochondrial proteostasis to maintain mitochondrial integrity and function by upregulating the expression of mitochondrial chaperones and proteases. We also determined whether nicotinamide riboside (NR), a NAD+ precursor, could mitigate ethanol-triggered cellular damage. When ImKCs were exposed to 80 mm ethanol for 72 h, they displayed inflammation, oxidative stress, and impaired mitochondrial function with decreased mitochondrial content and deformed mitochondrial crista structure. NR, however, counteracted the effects of ethanol. Furthermore, ethanol increased mRNA and protein levels of UPRmt genes, such as mitochondrial chaperones and proteases, which were attenuated by NR. Notably, the ethanol-induced shift in the entry of activating transcription factor 5 (ATF5), a putative transcriptional regulator of UPRmt, to the nucleus from the mitochondria was abolished by NR. The induction of UPRmt genes by ethanol was significantly repressed when Atf5 was knocked down, indicating the role of ATF5 in the induction of UPRmt genes in ImKCs exposed to ethanol. We also confirmed the induction of UPRmt gene expression in mouse and human livers exposed to alcohol. Our findings demonstrate the ability of NR to alleviate ethanol-induced oxidative stress, inflammation, and mitochondrial dysfunction, partly by modulating the ATF5-dependent UPRmt pathway in ImKCs, suggesting its potential for ALD therapy. © 2024 The Pathological Society of Great Britain and Ireland.
Collapse
Affiliation(s)
- Jaeeun Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Hayoung Woo
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Hyunju Kang
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
- Department of Food and Nutrition, Keimyung University, Daegu, South Korea
| | - Young-Ki Park
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| | - Ji-Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA
| |
Collapse
|
|
4
|
Kim H, Chen Q, Ju D, Purandare N, Chen X, Samavati L, Li L, Zhang R, Grossman LI, Zhang K. ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis. Proc Natl Acad Sci U S A 2024; 121:e2410486121. [PMID: 39589874 PMCID: PMC11626163 DOI: 10.1073/pnas.2410486121] [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: 06/03/2024] [Accepted: 10/28/2024] [Indexed: 11/28/2024] Open
Abstract
The Mitochondrial Unfolded Protein Response (UPRmt), a mitochondria-originated stress response to altered mitochondrial proteostasis, plays important roles in various pathophysiological processes. In this study, we revealed that the endoplasmic reticulum (ER)-tethered stress sensor CREBH regulates UPRmt to maintain mitochondrial homeostasis and function in the liver. CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion induced by energy demands. Under a fasting challenge or during the circadian cycle, CREBH is activated to promote expression of the genes encoding the key enzymes, chaperones, and regulators of UPRmt in the liver. Activated CREBH, cooperating with peroxisome proliferator-activated receptor α (PPARα), activates expression of Activating Transcription Factor (ATF) 5 and ATF4, two major UPRmt transcriptional regulators, independent of the ER-originated UPR (UPRER) pathways. Hepatic CREBH deficiency leads to accumulation of mitochondrial unfolded proteins, decreased mitochondrial membrane potential, and elevated cellular redox state. Dysregulation of mitochondrial function caused by CREBH deficiency coincides with increased hepatic mitochondrial oxidative phosphorylation (OXPHOS) but decreased glycolysis. CREBH knockout mice display defects in fatty acid oxidation and increased reliance on carbohydrate oxidation for energy production. In summary, our studies uncover that hepatic UPRmt is activated through CREBH under physiological challenges, highlighting a molecular link between ER and mitochondria in maintaining mitochondrial proteostasis and energy homeostasis under stress conditions.
Collapse
Affiliation(s)
- Hyunbae Kim
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI48201
| | - Qi Chen
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI48201
| | - Donghong Ju
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI48201
| | - Neeraja Purandare
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI48201
| | - Xuequn Chen
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI48201
| | - Lobelia Samavati
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI48201
| | - Li Li
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI48201
| | - Ren Zhang
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI48201
| | - Lawrence I. Grossman
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI48201
| | - Kezhong Zhang
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI48201
- Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI48201
| |
Collapse
|
|
5
|
Yu G, Huang Z, Guo C, Li J, Wang X, Wang Y, Wang X. Heat Shock Factor HSFA6b Mediates Mitochondrial Unfolded Protein Response in Arabidopsis thaliana. PLANTS (BASEL, SWITZERLAND) 2024; 13:3116. [PMID: 39599325 PMCID: PMC11597222 DOI: 10.3390/plants13223116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 10/11/2024] [Accepted: 10/19/2024] [Indexed: 11/29/2024]
Abstract
Mitochondria are important organelles in eukaryotes and are involved in various metabolic processes. Mitochondrial proteotoxic stress triggers the mitochondrial unfolded protein response (UPRmt) to restore mitochondrial protein homeostasis and maintain normal life activities. However, the regulatory mechanism of plant UPRmt remains to be revealed in Arabidopsis. Based on the fact that UPRmt activates heat shock protein (HSP) genes, we identified the heat shock transcription factor HSFA6b as a key regulator mediating UPRmt through reverse genetics. HSFA6b responded to mitochondrial proteotoxic stress and regulated mitochondrial heat shock proteins' genes' (mtHSPs) expression. HSFA6b translocated to the nuclear after treatment with doxycycline (Dox)-a mitochondrial ribosome translation inhibitor. HSFA6b binds to the mtHSPs promoters and activates mtHSPs expression. The HSFA6b mutation blocked the UPRmt signals to promote root growth under mitochondrial proteotoxic stress and accelerated leaf senescence during development. Our study reveals a novel signal-regulating mechanism in the UPRmt pathways and provides new insights regarding the regulation of plant growth and development and stress resistance by the UPRmt pathways.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Xu Wang
- Shanghai Collaborative Innovation Center of Agri-Seeds, Joint Center for Single Cell Biology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| |
Collapse
|
|
6
|
Da W, Chen Q, Shen B. The current insights of mitochondrial hormesis in the occurrence and treatment of bone and cartilage degeneration. Biol Res 2024; 57:37. [PMID: 38824571 PMCID: PMC11143644 DOI: 10.1186/s40659-024-00494-1] [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: 07/31/2023] [Accepted: 04/03/2024] [Indexed: 06/03/2024] Open
Abstract
It is widely acknowledged that aging, mitochondrial dysfunction, and cellular phenotypic abnormalities are intricately associated with the degeneration of bone and cartilage. Consequently, gaining a comprehensive understanding of the regulatory patterns governing mitochondrial function and its underlying mechanisms holds promise for mitigating the progression of osteoarthritis, intervertebral disc degeneration, and osteoporosis. Mitochondrial hormesis, referred to as mitohormesis, represents a cellular adaptive stress response mechanism wherein mitochondria restore homeostasis and augment resistance capabilities against stimuli by generating reactive oxygen species (ROS), orchestrating unfolded protein reactions (UPRmt), inducing mitochondrial-derived peptides (MDP), instigating mitochondrial dynamic changes, and activating mitophagy, all prompted by low doses of stressors. The varying nature, intensity, and duration of stimulus sources elicit divergent degrees of mitochondrial stress responses, subsequently activating one or more signaling pathways to initiate mitohormesis. This review focuses specifically on the effector molecules and regulatory networks associated with mitohormesis, while also scrutinizing extant mechanisms of mitochondrial dysfunction contributing to bone and cartilage degeneration through oxidative stress damage. Additionally, it underscores the potential of mechanical stimulation, intermittent dietary restrictions, hypoxic preconditioning, and low-dose toxic compounds to trigger mitohormesis, thereby alleviating bone and cartilage degeneration.
Collapse
Affiliation(s)
- Wacili Da
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Quan Chen
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Bin Shen
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| |
Collapse
|
|
7
|
Ahmad RN, Zhang LT, Morita R, Tani H, Wu Y, Chujo T, Ogawa A, Harada R, Shigeta Y, Tomizawa K, Wei FY. Pathological mutations promote proteolysis of mitochondrial tRNA-specific 2-thiouridylase 1 (MTU1) via mitochondrial caseinolytic peptidase (CLPP). Nucleic Acids Res 2024; 52:1341-1358. [PMID: 38113276 PMCID: PMC10853782 DOI: 10.1093/nar/gkad1197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 11/22/2023] [Accepted: 12/01/2023] [Indexed: 12/21/2023] Open
Abstract
MTU1 controls intramitochondrial protein synthesis by catalyzing the 2-thiouridine modification of mitochondrial transfer RNAs (mt-tRNAs). Missense mutations in the MTU1 gene are associated with life-threatening reversible infantile hepatic failure. However, the molecular pathogenesis is not well understood. Here, we investigated 17 mutations associated with this disease, and our results showed that most disease-related mutations are partial loss-of-function mutations, with three mutations being particularly severe. Mutant MTU1 is rapidly degraded by mitochondrial caseinolytic peptidase (CLPP) through a direct interaction with its chaperone protein CLPX. Notably, knockdown of CLPP significantly increased mutant MTU1 protein expression and mt-tRNA 2-thiolation, suggesting that accelerated proteolysis of mutant MTU1 plays a role in disease pathogenesis. In addition, molecular dynamics simulations demonstrated that disease-associated mutations may lead to abnormal intermolecular interactions, thereby impairing MTU1 enzyme activity. Finally, clinical data analysis underscores a significant correlation between patient prognosis and residual 2-thiolation levels, which is partially consistent with the AlphaMissense predictions. These findings provide a comprehensive understanding of MTU1-related diseases, offering prospects for modification-based diagnostics and novel therapeutic strategies centered on targeting CLPP.
Collapse
Affiliation(s)
- Raja Norazireen Raja Ahmad
- Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Kumamoto, 860-8556, Japan
- Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, 980-8575, Japan
| | - Long-Teng Zhang
- Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, 980-8575, Japan
| | - Rikuri Morita
- Center for Computational Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan
| | - Haruna Tani
- Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, 980-8575, Japan
| | - Yong Wu
- Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Kumamoto, 860-8556, Japan
| | - Takeshi Chujo
- Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Kumamoto, 860-8556, Japan
| | - Akiko Ogawa
- Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, 980-8575, Japan
| | - Ryuhei Harada
- Center for Computational Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan
| | - Yasuteru Shigeta
- Center for Computational Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8577, Japan
| | - Kazuhito Tomizawa
- Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Kumamoto, 860-8556, Japan
| | - Fan-Yan Wei
- Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, 980-8575, Japan
| |
Collapse
|
|
8
|
Min SH, Kang GM, Park JW, Kim MS. Beneficial Effects of Low-Grade Mitochondrial Stress on Metabolic Diseases and Aging. Yonsei Med J 2024; 65:55-69. [PMID: 38288646 PMCID: PMC10827639 DOI: 10.3349/ymj.2023.0131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 11/07/2023] [Accepted: 12/04/2023] [Indexed: 02/01/2024] Open
Abstract
Mitochondria function as platforms for bioenergetics, nutrient metabolism, intracellular signaling, innate immunity regulators, and modulators of stem cell activity. Thus, the decline in mitochondrial functions causes or correlates with diabetes mellitus and many aging-related diseases. Upon stress or damage, the mitochondria elicit a series of adaptive responses to overcome stress and restore their structural integrity and functional homeostasis. These adaptive responses to low-level or transient mitochondrial stress promote health and resilience to upcoming stress. Beneficial effects of low-grade mitochondrial stress, termed mitohormesis, have been observed in various organisms, including mammals. Accumulated evidence indicates that treatments boosting mitohormesis have therapeutic potential in various human diseases accompanied by mitochondrial stress. Here, we review multiple cellular signaling pathways and interorgan communication mechanisms through which mitochondrial stress leads to advantageous outcomes. We also discuss the relevance of mitohormesis in obesity, diabetes, metabolic liver disease, aging, and exercise.
Collapse
Affiliation(s)
- Se Hee Min
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Diabetes Center, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Korea
- Appetite Regulation Laboratory, Asan Institute for Life Science, Seoul, Korea
| | - Gil Myoung Kang
- Appetite Regulation Laboratory, Asan Institute for Life Science, Seoul, Korea
| | - Jae Woo Park
- Appetite Regulation Laboratory, Asan Institute for Life Science, Seoul, Korea
| | - Min-Seon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Diabetes Center, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Korea
- Appetite Regulation Laboratory, Asan Institute for Life Science, Seoul, Korea.
| |
Collapse
|
|
9
|
Chang CF, Gunawan AL, Liparulo I, Zushin PJH, Vitangcol K, Timblin GA, Saijo K, Wang B, Parlakgül G, Arruda AP, Stahl A. Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis. EMBO J 2024; 43:168-195. [PMID: 38212382 PMCID: PMC10897314 DOI: 10.1038/s44318-023-00008-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 10/27/2023] [Accepted: 11/08/2023] [Indexed: 01/13/2024] Open
Abstract
Coenzyme Q (CoQ) is essential for mitochondrial respiration and required for thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences of CoQ deficiency in specific tissues, such as BAT, remain poorly understood. Here, we show that pharmacological or genetic CoQ deficiency in BAT leads to stress signals causing accumulation of cytosolic mitochondrial RNAs and activation of the eIF2α kinase PKR, resulting in activation of the integrated stress response (ISR) with suppression of UCP1 but induction of FGF21 expression. Strikingly, despite diminished UCP1 levels, BAT CoQ deficiency displays increased whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high-fat diets (HFD). In line with enhanced metabolic rates, BAT and inguinal white adipose tissue (iWAT) interorgan crosstalk caused increased browning of iWAT in BAT-specific CoQ deficient animals. This mitohormesis-like effect depends on the ATF4-FGF21 axis and BAT-secreted FGF21, revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.
Collapse
Affiliation(s)
- Ching-Fang Chang
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, 94720, USA
| | - Amanda L Gunawan
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, 94720, USA
| | - Irene Liparulo
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, 94720, USA
| | - Peter-James H Zushin
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, 94720, USA
| | - Kaitlyn Vitangcol
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, 94720, USA
| | - Greg A Timblin
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Kaoru Saijo
- Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, 94720, USA
| | - Biao Wang
- Cardiovascular Research Institute, Department of Physiology, University of California, San Francisco, CA, 94158, USA
| | - Güneş Parlakgül
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, 94720, USA
| | - Ana Paula Arruda
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, 94720, USA
| | - Andreas Stahl
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, 94720, USA.
| |
Collapse
|
|
10
|
Atici AE, Crother TR, Noval Rivas M. Mitochondrial quality control in health and cardiovascular diseases. Front Cell Dev Biol 2023; 11:1290046. [PMID: 38020895 PMCID: PMC10657886 DOI: 10.3389/fcell.2023.1290046] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 10/16/2023] [Indexed: 12/01/2023] Open
Abstract
Cardiovascular diseases (CVDs) are one of the primary causes of mortality worldwide. An optimal mitochondrial function is central to supplying tissues with high energy demand, such as the cardiovascular system. In addition to producing ATP as a power source, mitochondria are also heavily involved in adaptation to environmental stress and fine-tuning tissue functions. Mitochondrial quality control (MQC) through fission, fusion, mitophagy, and biogenesis ensures the clearance of dysfunctional mitochondria and preserves mitochondrial homeostasis in cardiovascular tissues. Furthermore, mitochondria generate reactive oxygen species (ROS), which trigger the production of pro-inflammatory cytokines and regulate cell survival. Mitochondrial dysfunction has been implicated in multiple CVDs, including ischemia-reperfusion (I/R), atherosclerosis, heart failure, cardiac hypertrophy, hypertension, diabetic and genetic cardiomyopathies, and Kawasaki Disease (KD). Thus, MQC is pivotal in promoting cardiovascular health. Here, we outline the mechanisms of MQC and discuss the current literature on mitochondrial adaptation in CVDs.
Collapse
Affiliation(s)
- Asli E. Atici
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Timothy R. Crother
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Magali Noval Rivas
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children’s at Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| |
Collapse
|
|
11
|
Liu X, Ai Y, Xiao M, Wang C, Shu Z, Yin J, Chu Y, Xiao Q, Liu B. PM 2.5 juvenile exposure-induced spermatogenesis dysfunction by triggering testes ferroptosis and antioxidative vitamins intervention in adult male rats. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:111051-111061. [PMID: 37801247 PMCID: PMC10625507 DOI: 10.1007/s11356-023-30150-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 09/25/2023] [Indexed: 10/07/2023]
Abstract
PM2.5 derived from automobile exhaust can cause reproductive impairment in adult males, but the toxic effects of PM2.5 exposure on reproductive function in juvenile male rats and its relationship with ferroptosis have not been reported. In this paper, 30-day-old juvenile male Sprague-Dawley (SD) rats were divided into four groups (blank control, vitamin control, PM2.5, and PM2.5+Vitamin). The blank control group was fed normally, and the vitamin control group was given intragastric administration of vitamins in addition to normal feeding. PM2.5 was administered via tracheal intubation. When the rats were treated for 4 weeks until reaching the period of sexual maturity. A mating test was performed first, and then their testicular and epididymal tissues were studied. Compared with control rats, juvenile male rats exposed to PM2.5 showed a decreased sperm count and fertility rate, redox imbalance, damaged mitochondria, a metabolic disorder of intracellular iron ions, and a significant rise in ferroptosis during the period of sexual maturity. After antioxidative vitamins intervention, the redox imbalance, metabolic disorder of intracellular iron ions, and ferroptosis were all alleviated, leading to the following conclusions: after being exposed to PM2.5 from automobile exhaust, male juvenile rats during the period of sexual maturity have significantly decreased reproductive function. The reproductive toxicity of PM2.5 is closely related to oxidative stress and ferroptosis. In addition, ferroptosis decreases and reproductive function is recovered to some degree after antioxidative vitamins intervention.
Collapse
Affiliation(s)
- Xiang Liu
- Department of Pediatric Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
- Guizhou Children's Hospital, Zunyi, Guizhou Province, China
| | - Yaya Ai
- Department of Pediatric Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
- Guizhou Children's Hospital, Zunyi, Guizhou Province, China
| | - Mingchen Xiao
- Department of Pediatric Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
- Guizhou Children's Hospital, Zunyi, Guizhou Province, China
| | - Cao Wang
- Department of Pediatric Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
- Guizhou Children's Hospital, Zunyi, Guizhou Province, China
| | - Zhen Shu
- Department of Pediatric Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
- Guizhou Children's Hospital, Zunyi, Guizhou Province, China
| | - Jia Yin
- Suining Central Hospital, Suining, Sichuan Province, China
| | - Yu Chu
- Department of Pediatric Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
- Guizhou Children's Hospital, Zunyi, Guizhou Province, China
| | - Qing Xiao
- Department of Pediatric Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
- Guizhou Children's Hospital, Zunyi, Guizhou Province, China
| | - Bin Liu
- Department of Pediatric Surgery, Longgang District Maternity & Child Healthcare Hospital of Shenzhen City, Shenzhen, Guangdong Province, 518100, China.
- Department of Pediatric Surgery, Longgang Maternity and Child Institute of Shantou University Medical College, Shenzhen, Guangdong Province, 518100, China.
| |
Collapse
|
|
12
|
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.
Collapse
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
| |
Collapse
|
|
13
|
Li Y, Huang D, Jia L, Shangguan F, Gong S, Lan L, Song Z, Xu J, Yan C, Chen T, Tan Y, Liu Y, Huang X, Suzuki CK, Yang Z, Yang G, Lu B. LonP1 Links Mitochondria-ER Interaction to Regulate Heart Function. RESEARCH (WASHINGTON, D.C.) 2023; 6:0175. [PMID: 37333972 PMCID: PMC10275618 DOI: 10.34133/research.0175] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/29/2023] [Indexed: 06/20/2023]
Abstract
Interorganelle contacts and communications are increasingly recognized to play a vital role in cellular function and homeostasis. In particular, the mitochondria-endoplasmic reticulum (ER) membrane contact site (MAM) is known to regulate ion and lipid transfer, as well as signaling and organelle dynamics. However, the regulatory mechanisms of MAM formation and their function are still elusive. Here, we identify mitochondrial Lon protease (LonP1), a highly conserved mitochondrial matrix protease, as a new MAM tethering protein. The removal of LonP1 substantially reduces MAM formation and causes mitochondrial fragmentation. Furthermore, deletion of LonP1 in the cardiomyocytes of mouse heart impairs MAM integrity and mitochondrial fusion and activates the unfolded protein response within the ER (UPRER). Consequently, cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming and pathological heart remodeling. These findings demonstrate that LonP1 is a novel MAM-localized protein orchestrating MAM integrity, mitochondrial dynamics, and UPRER, offering exciting new insights into the potential therapeutic strategy for heart failure.
Collapse
Affiliation(s)
- Yujie Li
- The Affiliated Nanhua Hospital and School of Basic Medical Sciences, Hengyang Medical School,
University of South China, Hengyang, Hunan 421001, China
- School of Laboratory Medicine and Life Sciences,
Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- National Health Commission Key Laboratory of Birth Defect Research and Prevention,
Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan 410008, China
| | - Dawei Huang
- School of Laboratory Medicine and Life Sciences,
Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Lianqun Jia
- Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Ministry of Education of China,
Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110847, China
| | - Fugen Shangguan
- School of Laboratory Medicine and Life Sciences,
Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province,
The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shiwei Gong
- School of Laboratory Medicine and Life Sciences,
Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Linhua Lan
- School of Laboratory Medicine and Life Sciences,
Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province,
The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhiyin Song
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences,
Wuhan University, Wuhan, Hubei 430072, China
| | - Juan Xu
- Nanjing Maternity and Child Health Care Hospital,
Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing 210004, China
| | - Chaojun Yan
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences,
Wuhan University, Wuhan, Hubei 430072, China
| | - Tongke Chen
- Animal Center,
Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yin Tan
- Department of Cardiology,
The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Yongzhang Liu
- School of Laboratory Medicine and Life Sciences,
Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xingxu Huang
- School of Life Science and Technology,
Shanghai Tech University, Shanghai 201210, China
| | - Carolyn K. Suzuki
- Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School-Rutgers,
The State University of New Jersey, Newark, NJ, USA
| | - Zhongzhou Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center,
Nanjing University, Nanjing 210061, China
| | - Guanlin Yang
- Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Ministry of Education of China,
Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110847, China
| | - Bin Lu
- The Affiliated Nanhua Hospital and School of Basic Medical Sciences, Hengyang Medical School,
University of South China, Hengyang, Hunan 421001, China
- School of Laboratory Medicine and Life Sciences,
Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- National Health Commission Key Laboratory of Birth Defect Research and Prevention,
Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan 410008, China
| |
Collapse
|
|
14
|
Daglish SCD, Fennell EMJ, Graves LM. Targeting Mitochondrial DNA Transcription by POLRMT Inhibition or Depletion as a Potential Strategy for Cancer Treatment. Biomedicines 2023; 11:1598. [PMID: 37371693 PMCID: PMC10295849 DOI: 10.3390/biomedicines11061598] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 05/27/2023] [Accepted: 05/29/2023] [Indexed: 06/29/2023] Open
Abstract
Transcription of the mitochondrial genome is essential for the maintenance of oxidative phosphorylation (OXPHOS) and other functions directly related to this unique genome. Considerable evidence suggests that mitochondrial transcription is dysregulated in cancer and cancer metastasis and contributes significantly to cancer cell metabolism. Recently, inhibitors of the mitochondrial DNA-dependent RNA polymerase (POLRMT) were identified as potentially attractive new anti-cancer compounds. These molecules (IMT1, IMT1B) inactivate cancer cell metabolism through reduced transcription of mitochondrially-encoded OXPHOS subunits such as ND1-5 (Complex I) and COI-IV (Complex IV). Studies from our lab have discovered small molecule regulators of the mitochondrial matrix caseinolytic protease (ClpP) as probable inhibitors of mitochondrial transcription. These compounds activate ClpP proteolysis and lead to the rapid depletion of POLRMT and other matrix proteins, resulting in inhibition of mitochondrial transcription and growth arrest. Herein we present a comparison of POLRMT inhibition and ClpP activation, both conceptually and experimentally, and evaluate the results of these treatments on mitochondrial transcription, inhibition of OXPHOS, and ultimately cancer cell growth. We discuss the potential for targeting mitochondrial transcription as a cancer cell vulnerability.
Collapse
Affiliation(s)
| | | | - Lee M. Graves
- Department of Pharmacology and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (S.C.D.D.); (E.M.J.F.)
| |
Collapse
|
|
15
|
Kumar M, Sharma S, Mazumder S. Role of UPR mt and mitochondrial dynamics in host immunity: it takes two to tango. Front Cell Infect Microbiol 2023; 13:1135203. [PMID: 37260703 PMCID: PMC10227438 DOI: 10.3389/fcimb.2023.1135203] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 04/24/2023] [Indexed: 06/02/2023] Open
Abstract
The immune system of a host contains a group of heterogeneous cells with the prime aim of restraining pathogenic infection and maintaining homeostasis. Recent reports have proved that the various subtypes of immune cells exploit distinct metabolic programs for their functioning. Mitochondria are central signaling organelles regulating a range of cellular activities including metabolic reprogramming and immune homeostasis which eventually decree the immunological fate of the host under pathogenic stress. Emerging evidence suggests that following bacterial infection, innate immune cells undergo profound metabolic switching to restrain and countervail the bacterial pathogens, promote inflammation and restore tissue homeostasis. On the other hand, bacterial pathogens affect mitochondrial structure and functions to evade host immunity and influence their intracellular survival. Mitochondria employ several mechanisms to overcome bacterial stress of which mitochondrial UPR (UPRmt) and mitochondrial dynamics are critical. This review discusses the latest advances in our understanding of the immune functions of mitochondria against bacterial infection, particularly the mechanisms of mitochondrial UPRmt and mitochondrial dynamics and their involvement in host immunity.
Collapse
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
| | - Shibnath Mazumder
- Immunobiology Laboratory, Department of Zoology, University of Delhi, Delhi, India
- Faculty of Life Sciences and Biotechnology, South Asian University, Delhi, India
| |
Collapse
|
|
16
|
Fennell EMJ, Aponte-Collazo LJ, Pathmasiri W, Rushing BR, Barker NK, Partridge MC, Li YY, White CA, Greer YE, Herring LE, Lipkowitz S, Sumner SCJ, Iwanowicz EJ, Graves LM. Multi-omics analyses reveal ClpP activators disrupt essential mitochondrial pathways in triple-negative breast cancer. Front Pharmacol 2023; 14:1136317. [PMID: 37063293 PMCID: PMC10103842 DOI: 10.3389/fphar.2023.1136317] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 02/27/2023] [Indexed: 04/03/2023] Open
Abstract
ClpP activators ONC201 and related small molecules (TR compounds, Madera Therapeutics), have demonstrated significant anti-cancer potential in vitro and in vivo studies, including clinical trials for refractory solid tumors. Though progress has been made in identifying specific phenotypic outcomes following ClpP activation, the exact mechanism by which ClpP activation leads to broad anti-cancer activity has yet to be fully elucidated. In this study, we utilized a multi-omics approach to identify the ClpP-dependent proteomic, transcriptomic, and metabolomic changes resulting from ONC201 or the TR compound TR-57 in triple-negative breast cancer cells. Applying mass spectrometry-based methods of proteomics and metabolomics, we identified ∼8,000 proteins and 588 metabolites, respectively. From proteomics data, 113 (ONC201) and 191 (TR-57) proteins significantly increased and 572 (ONC201) and 686 (TR-57) proteins significantly decreased in this study. Gene ontological (GO) analysis revealed strong similarities between proteins up- or downregulated by ONC201 or TR-57 treatment. Notably, this included the downregulation of many mitochondrial processes and proteins, including mitochondrial translation and mitochondrial matrix proteins. We performed a large-scale transcriptomic analysis of WT SUM159 cells, identifying ∼7,700 transcripts (746 and 1,100 significantly increasing, 795 and 1,013 significantly decreasing in ONC201 and TR-57 treated cells, respectively). Less than 21% of these genes were affected by these compounds in ClpP null cells. GO analysis of these data demonstrated additional similarity of response to ONC201 and TR-57, including a decrease in transcripts related to the mitochondrial inner membrane and matrix, cell cycle, and nucleus, and increases in other nuclear transcripts and transcripts related to metal-ion binding. Comparison of response between both compounds demonstrated a highly similar response in all -omics datasets. Analysis of metabolites also revealed significant similarities between ONC201 and TR-57 with increases in α-ketoglutarate and 2-hydroxyglutaric acid and decreased ureidosuccinic acid, L-ascorbic acid, L-serine, and cytidine observed following ClpP activation in TNBC cells. Further analysis identified multiple pathways that were specifically impacted by ClpP activation, including ATF4 activation, heme biosynthesis, and the citrulline/urea cycle. In summary the results of our studies demonstrate that ONC201 and TR-57 induce highly similar and broad effects against multiple mitochondrial processes required for cell proliferation.
Collapse
Affiliation(s)
- Emily M. J. Fennell
- Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Lucas J. Aponte-Collazo
- Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Wimal Pathmasiri
- Department of Nutrition, Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, United States
| | - Blake R. Rushing
- Department of Nutrition, Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, United States
| | - Natalie K. Barker
- Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Michael Hooker Proteomics Core Facility, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Megan C. Partridge
- Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Yuan-Yuan Li
- Department of Nutrition, Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, United States
| | - Cody A. White
- Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Yoshimi E. Greer
- Women’s Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Laura E. Herring
- Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Michael Hooker Proteomics Core Facility, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Stanley Lipkowitz
- Women’s Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Susan C. J. Sumner
- Department of Nutrition, Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, United States
| | | | - Lee M. Graves
- Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- *Correspondence: Lee M. Graves,
| |
Collapse
|
|
17
|
The Crosstalk between Microbiome and Mitochondrial Homeostasis in Neurodegeneration. Cells 2023; 12:cells12030429. [PMID: 36766772 PMCID: PMC9913973 DOI: 10.3390/cells12030429] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/22/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
Mitochondria are highly dynamic organelles that serve as the primary cellular energy-generating system. Apart from ATP production, they are essential for many biological processes, including calcium homeostasis, lipid biogenesis, ROS regulation and programmed cell death, which collectively render them invaluable for neuronal integrity and function. Emerging evidence indicates that mitochondrial dysfunction and altered mitochondrial dynamics are crucial hallmarks of a wide variety of neurodevelopmental and neurodegenerative conditions. At the same time, the gut microbiome has been implicated in the pathogenesis of several neurodegenerative disorders due to the bidirectional communication between the gut and the central nervous system, known as the gut-brain axis. Here we summarize new insights into the complex interplay between mitochondria, gut microbiota and neurodegeneration, and we refer to animal models that could elucidate the underlying mechanisms, as well as novel interventions to tackle age-related neurodegenerative conditions, based on this intricate network.
Collapse
|
|
18
|
Chamseddine D, Mahmud SA, Westfall AK, Castoe TA, Berg RE, Pellegrino MW. The mitochondrial UPR regulator ATF5 promotes intestinal barrier function via control of the satiety response. Cell Rep 2022; 41:111789. [PMID: 36516750 PMCID: PMC9805788 DOI: 10.1016/j.celrep.2022.111789] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 09/08/2022] [Accepted: 11/16/2022] [Indexed: 12/14/2022] Open
Abstract
Organisms use several strategies to mitigate mitochondrial stress, including the activation of the mitochondrial unfolded protein response (UPRmt). The UPRmt in Caenorhabditis elegans, regulated by the transcription factor ATFS-1, expands on this recovery program by inducing an antimicrobial response against pathogens that target mitochondrial function. Here, we show that the mammalian ortholog of ATFS-1, ATF5, protects the host during infection with enteric pathogens but, unexpectedly, by maintaining the integrity of the intestinal barrier. Intriguingly, ATF5 supports intestinal barrier function by promoting a satiety response that prevents obesity and associated hyperglycemia. This consequently averts dysregulated glucose metabolism that is detrimental to barrier function. Mechanistically, we show that intestinal ATF5 stimulates the satiety response by transcriptionally regulating the gastrointestinal peptide hormone cholecystokinin, which promotes the secretion of the hormone leptin. We propose that ATF5 protects the host from enteric pathogens by promoting intestinal barrier function through a satiety-response-mediated metabolic control mechanism.
Collapse
Affiliation(s)
- Douja Chamseddine
- Department of Biology, University of Texas at Arlington, Arlington, TX 76019, USA
| | - Siraje A Mahmud
- Department of Biology, University of Texas at Arlington, Arlington, TX 76019, USA
| | - Aundrea K Westfall
- Department of Biology, University of Texas at Arlington, Arlington, TX 76019, USA
| | - Todd A Castoe
- Department of Biology, University of Texas at Arlington, Arlington, TX 76019, USA
| | - Rance E Berg
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Mark W Pellegrino
- Department of Biology, University of Texas at Arlington, Arlington, TX 76019, USA.
| |
Collapse
|
|
19
|
Tjahjono E, Kirienko DR, Kirienko NV. The emergent role of mitochondrial surveillance in cellular health. Aging Cell 2022; 21:e13710. [PMID: 36088658 PMCID: PMC9649602 DOI: 10.1111/acel.13710] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 08/12/2022] [Accepted: 08/29/2022] [Indexed: 01/25/2023] Open
Abstract
Mitochondrial dysfunction is one of the primary causatives for many pathologies, including neurodegenerative diseases, cancer, metabolic disorders, and aging. Decline in mitochondrial functions leads to the loss of proteostasis, accumulation of ROS, and mitochondrial DNA damage, which further exacerbates mitochondrial deterioration in a vicious cycle. Surveillance mechanisms, in which mitochondrial functions are closely monitored for any sign of perturbations, exist to anticipate possible havoc within these multifunctional organelles with primitive origin. Various indicators of unhealthy mitochondria, including halted protein import, dissipated membrane potential, and increased loads of oxidative damage, are on the top of the lists for close monitoring. Recent research also indicates a possibility of reductive stress being monitored as part of a mitochondrial surveillance program. Upon detection of mitochondrial stress, multiple mitochondrial stress-responsive pathways are activated to promote the transcription of numerous nuclear genes to ameliorate mitochondrial damage and restore compromised cellular functions. Co-expression occurs through functionalization of transcription factors, allowing their binding to promoter elements to initiate transcription of target genes. This review provides a comprehensive summary of the intricacy of mitochondrial surveillance programs and highlights their roles in our cellular life. Ultimately, a better understanding of these surveillance mechanisms is expected to improve healthspan.
Collapse
|
|
20
|
Zhou Z, Fan Y, Zong R, Tan K. The mitochondrial unfolded protein response: A multitasking giant in the fight against human diseases. Ageing Res Rev 2022; 81:101702. [PMID: 35908669 DOI: 10.1016/j.arr.2022.101702] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/15/2022] [Accepted: 07/26/2022] [Indexed: 02/06/2023]
Abstract
Mitochondria, which serve as the energy factories of cells, are involved in cell differentiation, calcium homeostasis, amino acid and fatty acid metabolism and apoptosis. In response to environmental stresses, mitochondrial homeostasis is regulated at both the organelle and molecular levels to effectively maintain the number and function of mitochondria. The mitochondrial unfolded protein response (UPRmt) is an adaptive intracellular stress mechanism that responds to stress signals by promoting the transcription of genes encoding mitochondrial chaperones and proteases. The mechanism of the UPRmt in Caenorhabditis elegans (C. elegans) has been clarified over time, and the main regulatory factors include ATFS-1, UBL-5 and DVE-1. In mammals, the activation of the UPRmt involves eIF2α phosphorylation and the uORF-regulated expression of CHOP, ATF4 and ATF5. Several additional factors, such as SIRT3 and HSF1, are also involved in regulating the UPRmt. A deep and comprehensive exploration of the UPRmt can provide new directions and strategies for the treatment of human diseases, including aging, neurodegenerative diseases, cardiovascular diseases and diabetes. In this review, we mainly discuss the function of UPRmt, describe the regulatory mechanisms of UPRmt in C. elegans and mammals, and summarize the relationship between UPRmt and various human diseases.
Collapse
Affiliation(s)
- Zixin Zhou
- Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Province Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, University of Chinese Academy of Sciences, Beijing, China
| | - Yumei Fan
- Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Province Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China
| | - Ruikai Zong
- Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Province Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China
| | - Ke Tan
- Key Laboratory of Molecular and Cellular Biology of Ministry of Education, Hebei Province Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei 050024, China.
| |
Collapse
|
|
21
|
Nedara K, Reinhardt C, Lebraud E, Arena G, Gracia C, Buard V, Pioche-Durieu C, Castelli F, Colsch B, Bénit P, Rustin P, Albaud B, Gestraud P, Baulande S, Servant N, Deutsch E, Verbavatz JM, Brenner C, Milliat F, Modjtahedi N. Relevance of the TRIAP1/p53 axis in colon cancer cell proliferation and adaptation to glutamine deprivation. Front Oncol 2022; 12:958155. [DOI: 10.3389/fonc.2022.958155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 10/10/2022] [Indexed: 11/13/2022] Open
Abstract
Human TRIAP1 (TP53-regulated inhibitor of apoptosis 1; also known as p53CSV for p53-inducible cell survival factor) is the homolog of yeast Mdm35, a well-known chaperone that interacts with the Ups/PRELI family proteins and participates in the intramitochondrial transfer of lipids for the synthesis of cardiolipin (CL) and phosphatidylethanolamine. Although recent reports indicate that TRIAP1 is a prosurvival factor abnormally overexpressed in various types of cancer, knowledge about its molecular and metabolic function in human cells is still elusive. It is therefore critical to understand the metabolic and proliferative advantages that TRIAP1 expression provides to cancer cells. Here, in a colorectal cancer cell model, we report that the expression of TRIAP1 supports cancer cell proliferation and tumorigenesis. Depletion of TRIAP1 perturbed the mitochondrial ultrastructure, without a major impact on CL levels and mitochondrial activity. TRIAP1 depletion caused extramitochondrial perturbations resulting in changes in the endoplasmic reticulum-dependent lipid homeostasis and induction of a p53-mediated stress response. Furthermore, we observed that TRIAP1 depletion conferred a robust p53-mediated resistance to the metabolic stress caused by glutamine deprivation. These findings highlight the importance of TRIAP1 in tumorigenesis and indicate that the loss of TRIAP1 has extramitochondrial consequences that could impact on the metabolic plasticity of cancer cells and their response to conditions of nutrient deprivation.
Collapse
|
|
22
|
Broxton CN, Kaur P, Lavorato M, Ganesh S, Xiao R, Mathew ND, Nakamaru-Ogiso E, Anderson VE, Falk MJ. Dichloroacetate and thiamine improve survival and mitochondrial stress in a C. elegans model of dihydrolipoamide dehydrogenase deficiency. JCI Insight 2022; 7:e156222. [PMID: 36278487 PMCID: PMC9714793 DOI: 10.1172/jci.insight.156222] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 09/12/2022] [Indexed: 01/16/2023] Open
Abstract
Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disorder caused by depletion of DLD from α-ketoacid dehydrogenase complexes. Caenorhabditis elegans animal models of DLD deficiency generated by graded feeding of dld-1(RNAi) revealed that full or partial reduction of DLD-1 expression recapitulated increased pyruvate levels typical of pyruvate dehydrogenase complex deficiency and significantly altered animal survival and health, with reductions in brood size, adult length, and neuromuscular function. DLD-1 deficiency dramatically increased mitochondrial unfolded protein stress response induction and adaptive mitochondrial proliferation. While ATP levels were reduced, respiratory chain enzyme activities and in vivo mitochondrial membrane potential were not significantly altered. DLD-1 depletion directly correlated with the induction of mitochondrial stress and impairment of worm growth and neuromuscular function. The safety and efficacy of dichloroacetate, thiamine, riboflavin, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), l-carnitine, and lipoic acid supplemental therapies empirically used for human DLD disease were objectively evaluated by life span and mitochondrial stress response studies. Only dichloroacetate and thiamine showed individual and synergistic therapeutic benefits. Collectively, these C. elegans dld-1(RNAi) animal model studies demonstrate the translational relevance of preclinical modeling of disease mechanisms and therapeutic candidates. Results suggest that clinical trials are warranted to evaluate the safety and efficacy of dichloroacetate and thiamine in human DLD disease.
Collapse
Affiliation(s)
- Chynna N. Broxton
- Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Prabhjot Kaur
- Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Manuela Lavorato
- Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Smruthi Ganesh
- Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | | | - Neal D. Mathew
- Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Eiko Nakamaru-Ogiso
- Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Vernon E. Anderson
- Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Marni J. Falk
- Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| |
Collapse
|
|
23
|
Hussain H, Djurin T, Rodriguez J, Daneelian L, Sundi S, Fadel A, Saadoon Z. Transactivation Response DNA-Binding Protein of 43 (TDP-43) and Glial Cell Roles in Neurological Disorders. Cureus 2022; 14:e30639. [DOI: 10.7759/cureus.30639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2022] [Indexed: 11/07/2022] Open
|
|
24
|
Kang Z, Chen F, Wu W, Liu R, Chen T, Xu F. UPRmt and coordinated UPRER in type 2 diabetes. Front Cell Dev Biol 2022; 10:974083. [PMID: 36187475 PMCID: PMC9523447 DOI: 10.3389/fcell.2022.974083] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
The mitochondrial unfolded protein response (UPRmt) is a molecular mechanism that maintains mitochondrial proteostasis under stress and is closely related to various metabolic diseases, such as type 2 diabetes (T2D). Similarly, the unfolded protein response of the endoplasmic reticulum (UPRER) is responsible for maintaining proteomic stability in the endoplasmic reticulum (ER). Since the mitochondria and endoplasmic reticulum are the primary centers of energy metabolism and protein synthesis in cells, respectively, a synergistic mechanism must exist between UPRmt and UPRER to cooperatively resist stresses such as hyperglycemia in T2D. Increasing evidence suggests that the protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK) signaling pathway is likely an important node for coordinating UPRmt and UPRER. The PERK pathway is activated in both UPRmt and UPRER, and its downstream molecules perform important functions. In this review, we discuss the mechanisms of UPRmt, UPRER and their crosstalk in T2D.
Collapse
Affiliation(s)
- Zhanfang Kang
- Department of Basic Medical Research, Qingyuan People’s Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, China
| | - Feng Chen
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Wanhui Wu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Rui Liu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Tianda Chen
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Fang Xu
- Department of Basic Medical Research, Qingyuan People’s Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- *Correspondence: Fang Xu,
| |
Collapse
|
|
25
|
Fennell EMJ, Aponte-Collazo LJ, Wynn JD, Drizyte-Miller K, Leung E, Greer YE, Graves PR, Iwanowicz AA, Ashamalla H, Holmuhamedov E, Lang H, Karanewsky DS, Der CJ, Houry WA, Lipkowitz S, Iwanowicz EJ, Graves LM. Characterization of TR-107, a novel chemical activator of the human mitochondrial protease ClpP. Pharmacol Res Perspect 2022; 10:e00993. [PMID: 35929764 PMCID: PMC9354705 DOI: 10.1002/prp2.993] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 06/03/2022] [Indexed: 11/25/2022] Open
Abstract
We recently described the identification of a new class of small‐molecule activators of the mitochondrial protease ClpP. These compounds synthesized by Madera Therapeutics showed increased potency of cancer growth inhibition over the related compound ONC201. In this study, we describe chemical optimization and characterization of the next generation of highly potent and selective small‐molecule ClpP activators (TR compounds) and demonstrate their efficacy against breast cancer models in vitro and in vivo. We selected one compound (TR‐107) with excellent potency, specificity, and drug‐like properties for further evaluation. TR‐107 showed ClpP‐dependent growth inhibition in the low nanomolar range that was equipotent to paclitaxel in triple‐negative breast cancer (TNBC) cell models. TR‐107 also reduced specific mitochondrial proteins, including OXPHOS and TCA cycle components, in a time‐, dose‐, and ClpP‐dependent manner. Seahorse XF analysis and glucose deprivation experiments confirmed the inactivation of OXPHOS and increased dependence on glycolysis following TR‐107 exposure. The pharmacokinetic properties of TR‐107 were compared with other known ClpP activators including ONC201 and ONC212. TR‐107 displayed excellent exposure and serum t1/2 after oral administration. Using human TNBC MDA‐MB‐231 xenografts, the antitumor response to TR‐107 was investigated. Oral administration of TR‐107 resulted in a reduction in tumor volume and extension of survival in the treated compared with vehicle control mice. ClpP activation in vivo was validated by immunoblotting for TFAM and other mitochondrial proteins. In summary, we describe the identification of highly potent new ClpP agonists with improved efficacy against TNBC, through targeted inactivation of OXPHOS and disruption of mitochondrial metabolism.
Collapse
Affiliation(s)
- Emily M J Fennell
- Department of Pharmacology and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Lucas J Aponte-Collazo
- Department of Pharmacology and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Joshua D Wynn
- Department of Pharmacology and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Kristina Drizyte-Miller
- Department of Pharmacology and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Elisa Leung
- Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
| | - Yoshimi Endo Greer
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Paul R Graves
- Department of Radiation Oncology, New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York, USA
| | | | - Hani Ashamalla
- Department of Radiation Oncology, New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York, USA
| | - Ekhson Holmuhamedov
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russian Federation
| | - Henk Lang
- Madera Therapeutics LLC, Chapel Hill, North Carolina, USA
| | | | - Channing J Der
- Department of Pharmacology and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Walid A Houry
- Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.,Department of Chemistry, University of Toronto, Toronto, Ontario, Canada
| | - Stanley Lipkowitz
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | | | - Lee M Graves
- Department of Pharmacology and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| |
Collapse
|
|
26
|
Suárez-Rivero JM, Pastor-Maldonado CJ, Povea-Cabello S, Álvarez-Córdoba M, Villalón-García I, Talaverón-Rey M, Suárez-Carrillo A, Munuera-Cabeza M, Reche-López D, Cilleros-Holgado P, Piñero-Perez R, Sánchez-Alcázar JA. UPR mt activation improves pathological alterations in cellular models of mitochondrial diseases. Orphanet J Rare Dis 2022; 17:204. [PMID: 35581596 PMCID: PMC9115953 DOI: 10.1186/s13023-022-02331-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 04/26/2022] [Indexed: 12/23/2022] Open
Abstract
Background Mitochondrial diseases represent one of the most common groups of genetic diseases. With a prevalence greater than 1 in 5000 adults, such diseases still lack effective treatment. Current therapies are purely palliative and, in most cases, insufficient. Novel approaches to compensate and, if possible, revert mitochondrial dysfunction must be developed. Results In this study, we tackled the issue using as a model fibroblasts from a patient bearing a mutation in the GFM1 gene, which is involved in mitochondrial protein synthesis. Mutant GFM1 fibroblasts could not survive in galactose restrictive medium for more than 3 days, making them the perfect screening platform to test several compounds. Tetracycline enabled mutant GFM1 fibroblasts survival under nutritional stress. Here we demonstrate that tetracycline upregulates the mitochondrial Unfolded Protein Response (UPRmt), a compensatory pathway regulating mitochondrial proteostasis. We additionally report that activation of UPRmt improves mutant GFM1 cellular bioenergetics and partially restores mitochondrial protein expression. Conclusions Overall, we provide compelling evidence to propose the activation of intrinsic cellular compensatory mechanisms as promising therapeutic strategy for mitochondrial diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-022-02331-8.
Collapse
Affiliation(s)
- Juan M Suárez-Rivero
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Carmen J Pastor-Maldonado
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Suleva Povea-Cabello
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Mónica Álvarez-Córdoba
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Irene Villalón-García
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Marta Talaverón-Rey
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Alejandra Suárez-Carrillo
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Manuel Munuera-Cabeza
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Diana Reche-López
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Paula Cilleros-Holgado
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - Rocío Piñero-Perez
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain
| | - José A Sánchez-Alcázar
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, 41013, Seville, Spain. .,Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, 41013, Seville, Spain.
| |
Collapse
|
|
27
|
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.
Collapse
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,
| |
Collapse
|
|
28
|
van der Stel W, Yang H, le Dévédec SE, van de Water B, Beltman JB, Danen EHJ. High-content high-throughput imaging reveals distinct connections between mitochondrial morphology and functionality for OXPHOS complex I, III, and V inhibitors. Cell Biol Toxicol 2022:10.1007/s10565-022-09712-6. [PMID: 35505273 DOI: 10.1007/s10565-022-09712-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 04/07/2022] [Indexed: 11/02/2022]
Abstract
Cells can adjust their mitochondrial morphology by altering the balance between mitochondrial fission and fusion to adapt to stressful conditions. The connection between a chemical perturbation, changes in mitochondrial function, and altered mitochondrial morphology is not well understood. Here, we made use of high-throughput high-content confocal microscopy to assess the effects of distinct classes of oxidative phosphorylation (OXPHOS) complex inhibitors on mitochondrial parameters in a concentration and time resolved manner. Mitochondrial morphology phenotypes were clustered based on machine learning algorithms and mitochondrial integrity patterns were mapped. In parallel, changes in mitochondrial membrane potential (MMP), mitochondrial and cellular ATP levels, and viability were microscopically assessed. We found that inhibition of MMP, mitochondrial ATP production, and oxygen consumption rate (OCR) using sublethal concentrations of complex I and III inhibitors did not trigger mitochondrial fragmentation. Instead, complex V inhibitors that suppressed ATP and OCR but increased MMP provoked a more fragmented mitochondrial morphology. In agreement, complex V but not complex I or III inhibitors triggered proteolytic cleavage of the mitochondrial fusion protein, OPA1. The relation between increased MMP and fragmentation did not extend beyond OXPHOS complex inhibitors: increasing MMP by blocking the mPTP pore did not lead to OPA1 cleavage or mitochondrial fragmentation and the OXPHOS uncoupler FCCP was associated with OPA1 cleavage and MMP reduction. Altogether, our findings connect vital mitochondrial functions and phenotypes in a high-throughput high-content confocal microscopy approach that help understanding of chemical-induced toxicity caused by OXPHOS complex perturbing chemicals.
Collapse
Affiliation(s)
- Wanda van der Stel
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Einsteinweg, 55, 2333 CC, Leiden, The Netherlands
| | - Huan Yang
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Einsteinweg, 55, 2333 CC, Leiden, The Netherlands
| | - Sylvia E le Dévédec
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Einsteinweg, 55, 2333 CC, Leiden, The Netherlands
| | - Bob van de Water
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Einsteinweg, 55, 2333 CC, Leiden, The Netherlands
| | - Joost B Beltman
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Einsteinweg, 55, 2333 CC, Leiden, The Netherlands
| | - Erik H J Danen
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Einsteinweg, 55, 2333 CC, Leiden, The Netherlands.
| |
Collapse
|
|
29
|
Yoon TK, Lee CH, Kwon O, Kim MS. Exercise, Mitohormesis, and Mitochondrial ORF of the 12S rRNA Type-C (MOTS-c). Diabetes Metab J 2022; 46:402-413. [PMID: 35656563 PMCID: PMC9171157 DOI: 10.4093/dmj.2022.0092] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 04/27/2022] [Indexed: 12/03/2022] Open
Abstract
Low levels of mitochondrial stress are beneficial for organismal health and survival through a process known as mitohormesis. Mitohormetic responses occur during or after exercise and may mediate some salutary effects of exercise on metabolism. Exercise-related mitohormesis involves reactive oxygen species production, mitochondrial unfolded protein response (UPRmt), and release of mitochondria-derived peptides (MDPs). MDPs are a group of small peptides encoded by mitochondrial DNA with beneficial metabolic effects. Among MDPs, mitochondrial ORF of the 12S rRNA type-c (MOTS-c) is the most associated with exercise. MOTS-c expression levels increase in skeletal muscles, systemic circulation, and the hypothalamus upon exercise. Systemic MOTS-c administration increases exercise performance by boosting skeletal muscle stress responses and by enhancing metabolic adaptation to exercise. Exogenous MOTS-c also stimulates thermogenesis in subcutaneous white adipose tissues, thereby enhancing energy expenditure and contributing to the anti-obesity effects of exercise training. This review briefly summarizes the mitohormetic mechanisms of exercise with an emphasis on MOTS-c.
Collapse
Affiliation(s)
- Tae Kwan Yoon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, H+ Yangji Hospital, Seoul, Korea
| | - Chan Hee Lee
- Department of of Biomedical Science & Program of Material Science for Medicine and Pharmaceutics, Hallym University, Chuncheon, Korea
| | - Obin Kwon
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Min-Seon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| |
Collapse
|
|
30
|
A high-resolution route map reveals distinct stages of chondrocyte dedifferentiation for cartilage regeneration. Bone Res 2022; 10:38. [PMID: 35477573 PMCID: PMC9046296 DOI: 10.1038/s41413-022-00209-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 01/24/2022] [Accepted: 02/28/2022] [Indexed: 11/09/2022] Open
Abstract
Articular cartilage damage is a universal health problem. Despite recent progress, chondrocyte dedifferentiation has severely compromised the clinical outcomes of cell-based cartilage regeneration. Loss-of-function changes are frequently observed in chondrocyte expansion and other pathological conditions, but the characteristics and intermediate molecular mechanisms remain unclear. In this study, we demonstrate a time-lapse atlas of chondrocyte dedifferentiation to provide molecular details and informative biomarkers associated with clinical chondrocyte evaluation. We performed various assays, such as single-cell RNA sequencing (scRNA-seq), live-cell metabolic assays, and assays for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), to develop a biphasic dedifferentiation model consisting of early and late dedifferentiation stages. Early-stage chondrocytes exhibited a glycolytic phenotype with increased expression of genes involved in metabolism and antioxidation, whereas late-stage chondrocytes exhibited ultrastructural changes involving mitochondrial damage and stress-associated chromatin remodeling. Using the chemical inhibitor BTB06584, we revealed that early and late dedifferentiated chondrocytes possessed distinct recovery potentials from functional phenotype loss. Notably, this two-stage transition was also validated in human chondrocytes. An image-based approach was established for clinical use to efficiently predict chondrocyte plasticity using stage-specific biomarkers. Overall, this study lays a foundation to improve the quality of chondrocytes in clinical use and provides deep insights into chondrocyte dedifferentiation.
Collapse
|
|
31
|
Taouktsi E, Kyriakou E, Smyrniotis S, Borbolis F, Bondi L, Avgeris S, Trigazis E, Rigas S, Voutsinas GE, Syntichaki P. Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease. Cells 2022; 11:cells11081363. [PMID: 35456042 PMCID: PMC9025075 DOI: 10.3390/cells11081363] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/09/2022] [Accepted: 04/14/2022] [Indexed: 02/01/2023] Open
Abstract
Cells engage complex surveillance mechanisms to maintain mitochondrial function and protein homeostasis. LonP1 protease is a key component of mitochondrial quality control and has been implicated in human malignancies and other pathological disorders. Here, we employed two experimental systems, the worm Caenorhabditis elegans and human cancer cells, to investigate and compare the effects of LONP-1/LonP1 deficiency at the molecular, cellular, and organismal levels. Deletion of the lonp-1 gene in worms disturbed mitochondrial function, provoked reactive oxygen species accumulation, and impaired normal processes, such as growth, behavior, and lifespan. The viability of lonp-1 mutants was dependent on the activity of the ATFS-1 transcription factor, and loss of LONP-1 evoked retrograde signaling that involved both the mitochondrial and cytoplasmic unfolded protein response (UPRmt and UPRcyt) pathways and ensuing diverse organismal stress responses. Exposure of worms to triterpenoid CDDO-Me, an inhibitor of human LonP1, stimulated only UPRcyt responses. In cancer cells, CDDO-Me induced key components of the integrated stress response (ISR), the UPRmt and UPRcyt pathways, and the redox machinery. However, genetic knockdown of LonP1 revealed a genotype-specific cellular response and induced apoptosis similar to CDDO-Me treatment. Overall, the mitochondrial dysfunction ensued by disruption of LonP1 elicits adaptive cytoprotective mechanisms that can inhibit cancer cell survival but diversely modulate organismal stress response and aging.
Collapse
Affiliation(s)
- Eirini Taouktsi
- Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece; (E.T.); (E.K.); (F.B.); (L.B.); (E.T.)
- Department of Biotechnology, Agricultural University of Athens, 11855 Athens, Greece;
| | - Eleni Kyriakou
- Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece; (E.T.); (E.K.); (F.B.); (L.B.); (E.T.)
| | - Stefanos Smyrniotis
- Laboratory of Molecular Carcinogenesis and Rare Disease Genetics, Institute of Biosciences and Applications, National Center for Scientific Research “Demokritos”, 15341 Athens, Greece; (S.S.); (S.A.)
| | - Fivos Borbolis
- Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece; (E.T.); (E.K.); (F.B.); (L.B.); (E.T.)
| | - Labrina Bondi
- Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece; (E.T.); (E.K.); (F.B.); (L.B.); (E.T.)
- Laboratory of Molecular Carcinogenesis and Rare Disease Genetics, Institute of Biosciences and Applications, National Center for Scientific Research “Demokritos”, 15341 Athens, Greece; (S.S.); (S.A.)
| | - Socratis Avgeris
- Laboratory of Molecular Carcinogenesis and Rare Disease Genetics, Institute of Biosciences and Applications, National Center for Scientific Research “Demokritos”, 15341 Athens, Greece; (S.S.); (S.A.)
| | - Efstathios Trigazis
- Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece; (E.T.); (E.K.); (F.B.); (L.B.); (E.T.)
| | - Stamatis Rigas
- Department of Biotechnology, Agricultural University of Athens, 11855 Athens, Greece;
| | - Gerassimos E. Voutsinas
- Laboratory of Molecular Carcinogenesis and Rare Disease Genetics, Institute of Biosciences and Applications, National Center for Scientific Research “Demokritos”, 15341 Athens, Greece; (S.S.); (S.A.)
- Correspondence: (G.E.V.); (P.S.); Tel.: +30-21-0650-3579 (G.E.V.); +30-21-0659-7474 (P.S.)
| | - Popi Syntichaki
- Laboratory of Molecular Genetics of Aging, Biomedical Research Foundation of the Academy of Athens, Center of Basic Research, 11527 Athens, Greece; (E.T.); (E.K.); (F.B.); (L.B.); (E.T.)
- Correspondence: (G.E.V.); (P.S.); Tel.: +30-21-0650-3579 (G.E.V.); +30-21-0659-7474 (P.S.)
| |
Collapse
|
|
32
|
Wachoski-Dark E, Zhao T, Khan A, Shutt TE, Greenway SC. Mitochondrial Protein Homeostasis and Cardiomyopathy. Int J Mol Sci 2022; 23:3353. [PMID: 35328774 PMCID: PMC8953902 DOI: 10.3390/ijms23063353] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/15/2022] [Accepted: 03/17/2022] [Indexed: 12/06/2022] Open
Abstract
Human mitochondrial disorders impact tissues with high energetic demands and can be associated with cardiac muscle disease (cardiomyopathy) and early mortality. However, the mechanistic link between mitochondrial disease and the development of cardiomyopathy is frequently unclear. In addition, there is often marked phenotypic heterogeneity between patients, even between those with the same genetic variant, which is also not well understood. Several of the mitochondrial cardiomyopathies are related to defects in the maintenance of mitochondrial protein homeostasis, or proteostasis. This essential process involves the importing, sorting, folding and degradation of preproteins into fully functional mature structures inside mitochondria. Disrupted mitochondrial proteostasis interferes with mitochondrial energetics and ATP production, which can directly impact cardiac function. An inability to maintain proteostasis can result in mitochondrial dysfunction and subsequent mitophagy or even apoptosis. We review the known mitochondrial diseases that have been associated with cardiomyopathy and which arise from mutations in genes that are important for mitochondrial proteostasis. Genes discussed include DnaJ heat shock protein family member C19 (DNAJC19), mitochondrial import inner membrane translocase subunit TIM16 (MAGMAS), translocase of the inner mitochondrial membrane 50 (TIMM50), mitochondrial intermediate peptidase (MIPEP), X-prolyl-aminopeptidase 3 (XPNPEP3), HtraA serine peptidase 2 (HTRA2), caseinolytic mitochondrial peptidase chaperone subunit B (CLPB) and heat shock 60-kD protein 1 (HSPD1). The identification and description of disorders with a shared mechanism of disease may provide further insights into the disease process and assist with the identification of potential therapeutics.
Collapse
Affiliation(s)
- Emily Wachoski-Dark
- Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada;
- Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Tian Zhao
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada;
| | - Aneal Khan
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada;
- Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
- M.A.G.I.C. Inc., Calgary, AB T2E 7Z4, Canada
| | - Timothy E. Shutt
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada;
- Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
- Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Steven C. Greenway
- Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada;
- Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada;
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada;
- Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
| |
Collapse
|
|
33
|
Yim J, Park SB. Label-Free Target Identification Reveals the Anticancer Mechanism of a Rhenium Isonitrile Complex. Front Chem 2022; 10:850638. [PMID: 35372261 PMCID: PMC8964423 DOI: 10.3389/fchem.2022.850638] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 02/25/2022] [Indexed: 01/21/2023] Open
Abstract
Elucidation of the molecular mechanism of therapeutic agents and potential candidates is in high demand. Interestingly, rhenium-based complexes have shown a highly selective anticancer effect, only on cancer cells, unlike platinum-based drugs, such as cisplatin and carboplatin. These differences might be attributed to their different molecular targets. We confirmed that the target of tricarbonyl rhenium isonitrile polypyridyl (TRIP) complex is a protein, not DNA, using ICP-MS analysis and identified heat shock protein 60 (HSP60) as its target protein using a label-free target identification method. The subsequent biological evaluation revealed that TRIP directly inhibits the chaperone function of HSP60 and induces the accumulation of misfolded proteins in mitochondria, thereby leading to the activation of mitochondrial unfolded protein response (mtUPR)-mediated JNK2/AP-1/CHOP apoptotic pathway.
Collapse
Affiliation(s)
- Junhyeong Yim
- Department of Biophysics and Chemical Biology, Seoul National University, Seoul, South Korea
| | - Seung Bum Park
- Department of Biophysics and Chemical Biology, Seoul National University, Seoul, South Korea
- CRI Center for Chemical Proteomics, Department of Chemistry, Seoul National University, Seoul, South Korea
- *Correspondence: Seung Bum Park,
| |
Collapse
|
|
34
|
Memme JM, Oliveira AN, Hood DA. p53 regulates skeletal muscle mitophagy and mitochondrial quality control following denervation-induced muscle disuse. J Biol Chem 2022; 298:101540. [PMID: 34958797 PMCID: PMC8790503 DOI: 10.1016/j.jbc.2021.101540] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/10/2021] [Accepted: 12/13/2021] [Indexed: 02/06/2023] Open
Abstract
Persistent inactivity promotes skeletal muscle atrophy, marked by mitochondrial aberrations that affect strength, mobility, and metabolic health leading to the advancement of disease. Mitochondrial quality control (MQC) pathways include biogenesis (synthesis), mitophagy/lysosomal turnover, and the mitochondrial unfolded protein response, which serve to maintain an optimal organelle network. Tumor suppressor p53 has been implicated in regulating muscle mitochondria in response to cellular stress; however, its role in the context of muscle disuse has yet to be explored, and whether p53 is necessary for MQC remains unclear. To address this, we subjected p53 muscle-specific KO (mKO) and WT mice to unilateral denervation. Transcriptomic and pathway analyses revealed dysregulation of pathways pertaining to mitochondrial function, and especially turnover, in mKO muscle following denervation. Protein and mRNA data of the MQC pathways indicated activation of the mitochondrial unfolded protein response and mitophagy-lysosome systems along with reductions in mitochondrial biogenesis and content in WT and mKO tissue following chronic denervation. However, p53 ablation also attenuated the expression of autophagy-mitophagy machinery, reduced autophagic flux, and enhanced lysosomal dysfunction. While similar reductions in mitochondrial biogenesis and content were observed between genotypes, MQC dysregulation exacerbated mitochondrial dysfunction in mKO fibers, evidenced by elevated reactive oxygen species. Moreover, acute experiments indicate that p53 mediates the expression of transcriptional regulators of MQC pathways as early as 1 day following denervation. Together, our data illustrate exacerbated mitochondrial dysregulation with denervation stress in p53 mKO tissue, thus indicating that p53 contributes to organellar maintenance via regulation of MQC pathways during muscle atrophy.
Collapse
Affiliation(s)
- Jonathan M Memme
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada
| | - Ashley N Oliveira
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada
| | - David A Hood
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
| |
Collapse
|
|
35
|
Hu D, Liu Z, Qi X. Mitochondrial Quality Control Strategies: Potential Therapeutic Targets for Neurodegenerative Diseases? Front Neurosci 2021; 15:746873. [PMID: 34867159 PMCID: PMC8633545 DOI: 10.3389/fnins.2021.746873] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 10/19/2021] [Indexed: 12/30/2022] Open
Abstract
Many lines of evidence have indicated the therapeutic potential of rescuing mitochondrial integrity by targeting specific mitochondrial quality control pathways in neurodegenerative diseases, such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. In addition to ATP synthesis, mitochondria are critical regulators of ROS production, lipid metabolism, calcium buffering, and cell death. The mitochondrial unfolded protein response, mitochondrial dynamics, and mitophagy are the three main quality control mechanisms responsible for maintaining mitochondrial proteostasis and bioenergetics. The proper functioning of these complex processes is necessary to surveil and restore mitochondrial homeostasis and the healthy pool of mitochondria in cells. Mitochondrial dysfunction occurs early and causally in disease pathogenesis. A significant accumulation of mitochondrial damage resulting from compromised quality control pathways leads to the development of neuropathology. Moreover, genetic or pharmaceutical manipulation targeting the mitochondrial quality control mechanisms can sufficiently rescue mitochondrial integrity and ameliorate disease progression. Thus, therapies that can improve mitochondrial quality control have great promise for the treatment of neurodegenerative diseases. In this review, we summarize recent progress in the field that underscores the essential role of impaired mitochondrial quality control pathways in the pathogenesis of neurodegenerative diseases. We also discuss the translational approaches targeting mitochondrial function, with a focus on the restoration of mitochondrial integrity, including mitochondrial dynamics, mitophagy, and mitochondrial proteostasis.
Collapse
Affiliation(s)
- Di Hu
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - Zunren Liu
- Department of Biology, College of Arts and Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Xin Qi
- Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, United States
- Center for Mitochondrial Disease, Case Western Reserve University School of Medicine, Cleveland, OH, United States
| |
Collapse
|
|
36
|
Lim Y, Berry B, Viteri S, McCall M, Park EC, Rongo C, Brookes PS, Nehrke K. FNDC-1-mediated mitophagy and ATFS-1 coordinate to protect against hypoxia-reoxygenation. Autophagy 2021; 17:3389-3401. [PMID: 33416042 PMCID: PMC8632273 DOI: 10.1080/15548627.2021.1872885] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 12/30/2020] [Accepted: 01/04/2021] [Indexed: 12/16/2022] Open
Abstract
Mitochondrial quality control (MQC) balances organelle adaptation and elimination, and mechanistic crosstalk between the underlying molecular processes affects subsequent stress outcomes. FUNDC1 (FUN14 domain containing 1) is a mammalian mitophagy receptor that responds to hypoxia-reoxygenation (HR) stress. Here, we provide evidence that FNDC-1 is the C. elegans ortholog of FUNDC1, and that its loss protects against injury in a worm model of HR. This protection depends upon ATFS-1, a transcription factor that is central to the mitochondrial unfolded protein response (UPRmt). Global mRNA and metabolite profiling suggest that atfs-1-dependent stress responses and metabolic remodeling occur in response to the loss of fndc-1. These data support a role for FNDC-1 in non-hypoxic MQC, and further suggest that these changes are prophylactic in relation to subsequent HR. Our results highlight functional coordination between mitochondrial adaptation and elimination that organizes stress responses and metabolic rewiring to protect against HR injury.Abbreviations: AL: autolysosome; AP: autophagosome; FUNDC1: FUN14 domain containing 1; HR: hypoxia-reperfusion; IR: ischemia-reperfusion; lof: loss of function; MQC: mitochondrial quality control; PCA: principle component analysis; PPP: pentonse phosphate pathway; proK (proteinase K);UPRmt: mitochondrial unfolded protein response; RNAi: RNA interference.
Collapse
Affiliation(s)
- Yunki Lim
- Medicine and Perioperative Medicine Departments, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, USA
| | - Brandon Berry
- Pharmacology and Physiology and Perioperative Medicine Departments, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, USA
| | - Stephanie Viteri
- Medicine and Perioperative Medicine Departments, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, USA
| | - Matthew McCall
- Biostatistics and Perioperative Medicine Departments, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, USA
| | - Eun Chan Park
- Department of Genetics , Waksman Institute/Rutgers University, Piscataway, New Jersey, USA
| | - Christopher Rongo
- Department of Genetics , Waksman Institute/Rutgers University, Piscataway, New Jersey, USA
| | - Paul S. Brookes
- Pharmacology and Physiology and Perioperative Medicine Departments, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, USA
- Anesthesiology, and Perioperative Medicine Departments, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, USA
| | - Keith Nehrke
- Medicine and Perioperative Medicine Departments, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, USA
- Pharmacology and Physiology and Perioperative Medicine Departments, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, USA
| |
Collapse
|
|
37
|
Oleson BJ, Bazopoulou D, Jakob U. Shaping longevity early in life: developmental ROS and H3K4me3 set the clock. Cell Cycle 2021; 20:2337-2347. [PMID: 34657571 PMCID: PMC8794500 DOI: 10.1080/15384101.2021.1986317] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Studies in Caenorhabditis elegans have revealed that even a genetically identical population of animals exposed to the same environment displays a remarkable level of variability in individual lifespan. Stochasticity factors, occurring seemingly by chance or at random, are thought to account for a large part of this variability. Recent studies in our lab using C. elegans now revealed that naturally occurring variations in the levels of reactive oxygen species experienced early in life contribute to the observed lifespan variability, and likely serve as stochasticity factors in aging. Here, we will highlight how developmental events can positively shape lifespan and stress responses via a redox-sensitive epigenetic regulator, and discuss the outstanding questions and future directions on the complex relationship between reactive oxygen species and aging.
Collapse
Affiliation(s)
- Bryndon J. Oleson
- Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, USA
| | - Daphne Bazopoulou
- Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, USA
| | - Ursula Jakob
- Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, USA,CONTACT Ursula Jakob Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, USA
| |
Collapse
|
|
38
|
Keerthiga R, Pei DS, Fu A. Mitochondrial dysfunction, UPR mt signaling, and targeted therapy in metastasis tumor. Cell Biosci 2021; 11:186. [PMID: 34717757 PMCID: PMC8556915 DOI: 10.1186/s13578-021-00696-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 10/02/2021] [Indexed: 12/13/2022] Open
Abstract
In modern research, mitochondria are considered a more crucial energy plant in cells. Mitochondrial dysfunction, including mitochondrial DNA (mtDNA) mutation and denatured protein accumulation, is a common feature of tumors. The dysfunctional mitochondria reprogram molecular metabolism and allow tumor cells to proliferate in the hostile microenvironment. One of the crucial signaling pathways of the mitochondrial dysfunction activation in the tumor cells is the retrograde signaling of mitochondria-nucleus interaction, mitochondrial unfolded protein response (UPRmt), which is initiated by accumulation of denatured protein and excess ROS production. In the process of UPRmt, various components are activitated to enhance the mitochondria-nucleus retrograde signaling to promote carcinoma progression, including hypoxia-inducible factor (HIF), activating transcription factor ATF-4, ATF-5, CHOP, AKT, AMPK. The retrograde signaling molecules of overexpression ATF-5, SIRT3, CREB, SOD1, SOD2, early growth response protein 1 (EGR1), ATF2, CCAAT/enhancer-binding protein-d, and CHOP also involved in the process. Targeted blockage of the UPRmt pathway could obviously inhibit tumor proliferation and metastasis. This review indicates the UPRmt pathways and its crucial role in targeted therapy of metastasis tumors.
Collapse
Affiliation(s)
| | - De-Sheng Pei
- School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, China.
| | - Ailing Fu
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
| |
Collapse
|
|
39
|
van der Stel W, Yang H, Vrijenhoek NG, Schimming JP, Callegaro G, Carta G, Darici S, Delp J, Forsby A, White A, le Dévédec S, Leist M, Jennings P, Beltman JB, van de Water B, Danen EHJ. Mapping the cellular response to electron transport chain inhibitors reveals selective signaling networks triggered by mitochondrial perturbation. Arch Toxicol 2021; 96:259-285. [PMID: 34642769 PMCID: PMC8748354 DOI: 10.1007/s00204-021-03160-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 09/09/2021] [Indexed: 12/24/2022]
Abstract
Mitochondrial perturbation is a key event in chemical-induced organ toxicities that is incompletely understood. Here, we studied how electron transport chain (ETC) complex I, II, or III (CI, CII and CIII) inhibitors affect mitochondrial functionality, stress response activation, and cell viability using a combination of high-content imaging and TempO-Seq in HepG2 hepatocyte cells. CI and CIII inhibitors perturbed mitochondrial membrane potential (MMP) and mitochondrial and cellular ATP levels in a concentration- and time-dependent fashion and, under conditions preventing a switch to glycolysis attenuated cell viability, whereas CII inhibitors had no effect. TempO-Seq analysis of changes in mRNA expression pointed to a shared cellular response to CI and CIII inhibition. First, to define specific ETC inhibition responses, a gene set responsive toward ETC inhibition (and not to genotoxic, oxidative, or endoplasmic reticulum stress) was identified using targeted TempO-Seq in HepG2. Silencing of one of these genes, NOS3, exacerbated the impact of CI and CIII inhibitors on cell viability, indicating its functional implication in cellular responses to mitochondrial stress. Then by monitoring dynamic responses to ETC inhibition using a HepG2 GFP reporter panel for different classes of stress response pathways and applying pathway and gene network analysis to TempO-Seq data, we looked for downstream cellular events of ETC inhibition and identified the amino acid response (AAR) as being triggered in HepG2 by ETC inhibition. Through in silico approaches we provide evidence indicating that a similar AAR is associated with exposure to mitochondrial toxicants in primary human hepatocytes. Altogether, we (i) unravel quantitative, time- and concentration-resolved cellular responses to mitochondrial perturbation, (ii) identify a gene set associated with adaptation to exposure to active ETC inhibitors, and (iii) show that ER stress and an AAR accompany ETC inhibition in HepG2 and primary hepatocytes.
Collapse
Affiliation(s)
- Wanda van der Stel
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The Netherlands
| | - Huan Yang
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The Netherlands
| | - Nanette G Vrijenhoek
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The Netherlands
| | - Johannes P Schimming
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The Netherlands
| | - Giulia Callegaro
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The Netherlands
| | - Giada Carta
- Division Molecular and Computational Toxicology, Vrije University Amsterdam, Amsterdam, The Netherlands
| | - Salihanur Darici
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The Netherlands
| | - Johannes Delp
- Chair for In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, Konstanz, Germany
| | - Anna Forsby
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | | | - Sylvia le Dévédec
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The Netherlands
| | - Marcel Leist
- Chair for In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, Konstanz, Germany
| | - Paul Jennings
- Division Molecular and Computational Toxicology, Vrije University Amsterdam, Amsterdam, The Netherlands
| | - Joost B Beltman
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The Netherlands
| | - Bob van de Water
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The Netherlands.
| | - Erik H J Danen
- Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The Netherlands.
| |
Collapse
|
|
40
|
Adaptive optimization of the OXPHOS assembly line partially compensates lrpprc-dependent mitochondrial translation defects in mice. Commun Biol 2021; 4:989. [PMID: 34413467 PMCID: PMC8376967 DOI: 10.1038/s42003-021-02492-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 07/20/2021] [Indexed: 11/20/2022] Open
Abstract
Mouse models of genetic mitochondrial disorders are generally used to understand specific molecular defects and their biochemical consequences, but rarely to map compensatory changes allowing survival. Here we took advantage of the extraordinary mitochondrial resilience of hepatic Lrpprc knockout mice to explore this question using native proteomics profiling and lipidomics. In these mice, low levels of the mtRNA binding protein LRPPRC induce a global mitochondrial translation defect and a severe reduction (>80%) in the assembly and activity of the electron transport chain (ETC) complex IV (CIV). Yet, animals show no signs of overt liver failure and capacity of the ETC is preserved. Beyond stimulation of mitochondrial biogenesis, results show that the abundance of mitoribosomes per unit of mitochondria is increased and proteostatic mechanisms are induced in presence of low LRPPRC levels to preserve a balance in the availability of mitochondrial- vs nuclear-encoded ETC subunits. At the level of individual organelles, a stabilization of residual CIV in supercomplexes (SCs) is observed, pointing to a role of these supramolecular arrangements in preserving ETC function. While the SC assembly factor COX7A2L could not contribute to the stabilization of CIV, important changes in membrane glycerophospholipid (GPL), most notably an increase in SC-stabilizing cardiolipins species (CLs), were observed along with an increased abundance of other supramolecular assemblies known to be stabilized by, and/or participate in CL metabolism. Together these data reveal a complex in vivo network of molecular adjustments involved in preserving mitochondrial integrity in energy consuming organs facing OXPHOS defects, which could be therapeutically exploited. Cuillerier et al. investigate compensatory mechanisms underlying survival of mice with a liver-specific knockout of the mitochondrial mRNA-binding protein Lrpprc. They propose various mechanisms operating along the OXPHOS assembly line, including mitochondrial biogenesis, mitochondrial ribosome upregulation and preferential supercomplex assembly, that could compensate lack of LRPPRC and allow survival of these mice.
Collapse
|
|
41
|
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.
Collapse
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.
| |
Collapse
|
|
42
|
Li W, Gong M, Park YP, Elshikha AS, Choi SC, Brown J, Kanda N, Yeh WI, Peters L, Titov AA, Teng X, Brusko TM, Morel L. Lupus susceptibility gene Esrrg modulates regulatory T cells through mitochondrial metabolism. JCI Insight 2021; 6:e143540. [PMID: 34156979 PMCID: PMC8410062 DOI: 10.1172/jci.insight.143540] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 06/16/2021] [Indexed: 01/31/2023] Open
Abstract
Estrogen-related receptor γ (Esrrg) is a murine lupus susceptibility gene associated with T cell activation. Here, we report that Esrrg controls Tregs through mitochondria homeostasis. Esrrg deficiency impaired the maintenance and function of Tregs, leading to global T cell activation and autoimmunity in aged mice. Further, Esrrg-deficient Tregs presented an impaired differentiation into follicular Tregs that enhanced follicular helper T cells' responses. Mechanistically, Esrrg-deficient Tregs presented with dysregulated mitochondria with decreased oxygen consumption as well as ATP and NAD+ production. In addition, Esrrg-deficient Tregs exhibited decreased phosphatidylinositol and TGF-β signaling pathways and increased mTOR complex 1 activation. We found that the expression of human ESRRG, which is high in Tregs, was lower in CD4+ T cells from patients with lupus than in healthy controls. Finally, knocking down ESRRG in Jurkat T cells decreased their metabolism. Together, our results reveal a critical role of Esrrg in the maintenance and metabolism of Tregs, which may provide a genetic link between lupus pathogenesis and mitochondrial dysfunction in T cells.
Collapse
Affiliation(s)
- Wei Li
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Minghao Gong
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Yuk Pheel Park
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Ahmed S Elshikha
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA.,Department of Pharmaceutics, Zagazig University, Zagazig, Egypt
| | - Seung-Chul Choi
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Josephine Brown
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Nathalie Kanda
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Wen-I Yeh
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Leeana Peters
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Anton A Titov
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Xiangyu Teng
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Todd M Brusko
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Laurence Morel
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| |
Collapse
|
|
43
|
Mitochondria and Antibiotics: For Good or for Evil? Biomolecules 2021; 11:biom11071050. [PMID: 34356674 PMCID: PMC8301944 DOI: 10.3390/biom11071050] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/12/2021] [Accepted: 07/15/2021] [Indexed: 01/16/2023] Open
Abstract
The discovery and application of antibiotics in the common clinical practice has undeniably been one of the major medical advances in our times. Their use meant a drastic drop in infectious diseases-related mortality and contributed to prolonging human life expectancy worldwide. Nevertheless, antibiotics are considered by many a double-edged sword. Their extensive use in the past few years has given rise to a global problem: antibiotic resistance. This factor and the increasing evidence that a wide range of antibiotics can damage mammalian mitochondria, have driven a significant sector of the medical and scientific communities to advise against the use of antibiotics for purposes other to treating severe infections. Notwithstanding, a notorious number of recent studies support the use of these drugs to treat very diverse conditions, ranging from cancer to neurodegenerative or mitochondrial diseases. In this context, there is great controversy on whether the risks associated to antibiotics outweigh their promising beneficial features. The aim of this review is to provide insight in the topic, purpose for which the most relevant findings regarding antibiotic therapies have been discussed.
Collapse
|
|
44
|
Lopez-Crisosto C, Díaz-Vegas A, Castro PF, Rothermel BA, Bravo-Sagua R, Lavandero S. Endoplasmic reticulum-mitochondria coupling increases during doxycycline-induced mitochondrial stress in HeLa cells. Cell Death Dis 2021; 12:657. [PMID: 34183648 PMCID: PMC8238934 DOI: 10.1038/s41419-021-03945-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 06/16/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023]
Abstract
Subcellular organelles communicate with each other to regulate function and coordinate responses to changing cellular conditions. The physical-functional coupling of the endoplasmic reticulum (ER) with mitochondria allows for the direct transfer of Ca2+ between organelles and is an important avenue for rapidly increasing mitochondrial metabolic activity. As such, increasing ER-mitochondrial coupling can boost the generation of ATP that is needed to restore homeostasis in the face of cellular stress. The mitochondrial unfolded protein response (mtUPR) is activated by the accumulation of unfolded proteins in mitochondria. Retrograde signaling from mitochondria to the nucleus promotes mtUPR transcriptional responses aimed at restoring protein homeostasis. It is currently unknown whether the changes in mitochondrial-ER coupling also play a role during mtUPR stress. We hypothesized that mitochondrial stress favors an expansion of functional contacts between mitochondria and ER, thereby increasing mitochondrial metabolism as part of a protective response. Hela cells were treated with doxycycline, an antibiotic that inhibits the translation of mitochondrial-encoded proteins to create protein disequilibrium. Treatment with doxycycline decreased the abundance of mitochondrial encoded proteins while increasing expression of CHOP, C/EBPβ, ClpP, and mtHsp60, markers of the mtUPR. There was no change in either mitophagic activity or cell viability. Furthermore, ER UPR was not activated, suggesting focused activation of the mtUPR. Within 2 h of doxycycline treatment, there was a significant increase in physical contacts between mitochondria and ER that was distributed throughout the cell, along with an increase in the kinetics of mitochondrial Ca2+ uptake. This was followed by the rise in the rate of oxygen consumption at 4 h, indicating a boost in mitochondrial metabolic activity. In conclusion, an early phase of the response to doxycycline-induced mitochondrial stress is an increase in mitochondrial-ER coupling that potentiates mitochondrial metabolic activity as a means to support subsequent steps in the mtUPR pathway and sustain cellular adaptation.
Collapse
Affiliation(s)
- Camila Lopez-Crisosto
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmaceuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alexis Díaz-Vegas
- Charles Perkins Centre, School of Life and Environmental Sciences, The University of Sydney, Camperdown, 2050, Sydney, NSW, Australia
| | - Pablo F Castro
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Corporacion Centro de Estudios Científicos de las Enfermedades Cronicas (CECEC), Santiago, 7680201, Chile
| | - Beverly A Rothermel
- Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Roberto Bravo-Sagua
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmaceuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, 7830490, Chile
- Chilean State Universities Network on Aging, Universidad de Chile, Santiago, Chile
| | - Sergio Lavandero
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmaceuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.
- Corporacion Centro de Estudios Científicos de las Enfermedades Cronicas (CECEC), Santiago, 7680201, Chile.
- Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, TX, USA.
| |
Collapse
|
|
45
|
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.
Collapse
|
|
46
|
Sapkota M, Adnan Qureshi M, Arif Mahmud S, Balikosa Y, Nguyen C, Boll JM, Pellegrino MW. A nematode-derived, mitochondrial stress signaling-regulated peptide exhibits broad antibacterial activity. Biol Open 2021; 10:268320. [PMID: 34184732 PMCID: PMC8181894 DOI: 10.1242/bio.058613] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 04/06/2021] [Indexed: 12/11/2022] Open
Abstract
A dramatic rise of infections with antibiotic-resistant bacterial pathogens continues to challenge the healthcare field due to the lack of effective treatment regimes. As such, there is an urgent need to develop new antimicrobial agents that can combat these multidrug-resistant superbugs. Mitochondria are central regulators of metabolism and other cellular functions, including the regulation of innate immunity pathways involved in the defense against infection. The mitochondrial unfolded protein response (UPRmt) is a stress-activated pathway that mitigates mitochondrial dysfunction through the regulation of genes that promote recovery of the organelle. In the model organism Caenorhabditis elegans, the UPRmt also mediates an antibacterial defense program that combats pathogen infection, which promotes host survival. We sought to identify and characterize antimicrobial effectors that are regulated during the UPRmt. From our search, we discovered that the antimicrobial peptide CNC-4 is upregulated during this stress response. CNC-4 belongs to the caenacin family of antimicrobial peptides, which are predominantly found in nematodes and are known to have anti-fungal properties. Here, we find that CNC-4 also possesses potent antimicrobial activity against a spectrum of bacterial species and report on its characterization. Summary: The caenacin antimicrobial peptide CNC-4 is regulated by a mitochondrial recovery pathway and exhibits broad antibacterial activity.
Collapse
Affiliation(s)
- Madhab Sapkota
- Department of Biology, University of Texas Arlington, Arlington, 76019 Texas, USA
| | | | - Siraje Arif Mahmud
- Department of Biology, University of Texas Arlington, Arlington, 76019 Texas, USA
| | - Yves Balikosa
- Department of Biology, University of Texas Arlington, Arlington, 76019 Texas, USA
| | - Charlton Nguyen
- Department of Biology, University of Texas Arlington, Arlington, 76019 Texas, USA
| | - Joseph M Boll
- Department of Biology, University of Texas Arlington, Arlington, 76019 Texas, USA
| | - Mark W Pellegrino
- Department of Biology, University of Texas Arlington, Arlington, 76019 Texas, USA
| |
Collapse
|
|
47
|
Yu Z, Hou Y, Zhou W, Zhao Z, Liu Z, Fu A. The effect of mitochondrial transplantation therapy from different gender on inhibiting cell proliferation of malignant melanoma. Int J Biol Sci 2021; 17:2021-2033. [PMID: 34131403 PMCID: PMC8193273 DOI: 10.7150/ijbs.59581] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 04/23/2021] [Indexed: 01/16/2023] Open
Abstract
Today mitochondria are considered much more than a energy plant in cells. Mitochondrial transplantation therapy has been an active research area for treating mitochondria-associated diseases from animal studies to clinical trials. However, the specific mechanism involved in the anti-tumor activity of healthy mitochondria remain to be characterized. Here we investigate the signal mechanism and gender difference of mitochondrial transplantation therapy against malignant melanoma. In the study, we administrated intact mitochondria extracted from mouse livers respectively to the mice bearing malignantly subcutaneous and metastatic melanoma, and identified the signal mechanism responsible for the mitochondrial treatment through transcriptomic analysis. Meanwhile, the efficiency of female mitochondria and male mitochondria was compared in the cultured melanoma cells and transplanted melanoma in mice. The results suggested that the mitochondria significantly inhibited the tumor cell proliferation in vitro through cell cycle arrest and induction of cell apoptosis. In the melanoma-bearing mice, the mitochondria retard the tumor growth and lung migration, and the transcriptomic analysis indicated that general chromosome silencing was strongly associated with the mitochondria against melanoma after the mitochondrial transplantation on the metastasis melanoma. Moreover, the anti-tumor activity of mitochondria from female animals was more efficient in comparison to the males, and the female mitochondria could probably induce more persuasive mitochondria-nuclear communication than the mitochondria from male mice. The study identifies the anti-tumor mechanism of the mitochondrial transplantation therapy, and provides a novel insight into the effect of mitochondria from different gender.
Collapse
Affiliation(s)
| | | | | | | | | | - Ailing Fu
- School of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| |
Collapse
|
|
48
|
Rotko D, Kudin AP, Zsurka G, Kulawiak B, Szewczyk A, Kunz WS. Molecular and Functional Effects of Loss of Cytochrome c Oxidase Subunit 8A. BIOCHEMISTRY (MOSCOW) 2021; 86:33-43. [PMID: 33705280 DOI: 10.1134/s0006297921010041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
In this work we studied molecular and functional effects of the loss of the smallest nuclear encoded subunit of cytochrome c oxidase COX8A in fibroblasts from a patient with a homozygous splice site mutation and in CRISPR/Cas9 genome-edited HEK293T cells. In both cellular model systems, between 20 to 30% of the residual enzymatic activity of cytochrome c oxidase (COX) was detectable. In immunoblots of BN-PAGE separated mitochondria from both cellular models almost no monomers and dimers of the fully assembled COX could be visualized. Interestingly, supercomplexes of COX formed with complex III and also with complexes I and III retained considerable immunoreactivity, while nearly no immunoreactivity attributable to subassemblies was found. That indicates that COX lacking subunit 8A is stabilized in supercomplexes, while monomers and dimers are rapidly degraded. With transcriptome analysis by 3'-RNA sequencing we failed to detect in our cellular models of COX8A deficiency transcriptional changes of genes involved in the mitochondrial unfolded protein response (mtUPR) and the integrated stress response (ISR). Thus, our data strongly suggest that the smallest subunit of cytochrome c oxidase COX8A is required for maintenance of the structural stability of COX monomers and dimers.
Collapse
Affiliation(s)
- Daria Rotko
- Institute of Experimental Epileptology and Cognition Research, Life & Brain Center, University of Bonn, Venusberg-Campus 1, Bonn, 53127, Germany. .,Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, 02-093, Poland
| | - Alexei P Kudin
- Institute of Experimental Epileptology and Cognition Research, Life & Brain Center, University of Bonn, Venusberg-Campus 1, Bonn, 53127, Germany.
| | - Gábor Zsurka
- Institute of Experimental Epileptology and Cognition Research, Life & Brain Center, University of Bonn, Venusberg-Campus 1, Bonn, 53127, Germany. .,Department of Epileptology, University Bonn Medical Center, Venusberg-Campus 1, Bonn, 53127, Germany
| | - Bogusz Kulawiak
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, 02-093, Poland.
| | - Adam Szewczyk
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, 02-093, Poland.
| | - Wolfram S Kunz
- Institute of Experimental Epileptology and Cognition Research, Life & Brain Center, University of Bonn, Venusberg-Campus 1, Bonn, 53127, Germany. .,Department of Epileptology, University Bonn Medical Center, Venusberg-Campus 1, Bonn, 53127, Germany
| |
Collapse
|
|
49
|
Zhao Y, Li MZ, Talukder M, Luo Y, Shen Y, Wang HR, Li JL. Effect of mitochondrial quality control on the lycopene antagonizing DEHP-induced mitophagy in spermatogenic cells. Food Funct 2021; 11:5815-5826. [PMID: 32602507 DOI: 10.1039/d0fo00554a] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Di(2-ethylhexyl) phthalate (DEHP) is a widespread environmental contaminant, which is mainly used as a plasticizer to improve the flexibility of products; however, its extensive use causes male reproductive damage. Lycopene (LYC) has a protective effect on male reproductive toxicity. Nevertheless, the underlying role of LYC in DEHP-induced spermatogenic cell damage remains unclear. Our study aimed to investigate the role of LYC in DEHP-induced spermatogenic cell damage and its underlying mechanism. Male ICR mice were treated with LYC (5 mg kg-1) and/or DEHP (500 mg kg-1 or 1000 mg kg-1) for 28 days. The results showed that LYC alleviated the DEHP-induced decrease in mitochondria volume density and mitochondrial membrane potential (ΔΨm). Subsequently, LYC prevented the DEHP-induced PGC-1α-mediated reduction in mitochondrial biogenesis in spermatogenic cells. LYC exhibited a potential preventive effect against DEHP-induced mitophagy caused by mitochondrial dynamics disorder in the spermatogenic cells. Meanwhile, LYC relieved DEHP-induced mitochondrial stress in the spermatogenic cells by activating UPRmt. These results proved that mitochondrial quality control may be related to the beneficial role of LYC in preventing DEHP-induced mitophagy in spermatogenic cells. This study provides new evidence of mitochondrial quality control as a target for LYC treatment, which can prevent DEHP-induced toxicity.
Collapse
Affiliation(s)
- Yi Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
| | - Mu-Zi Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
| | - Milton Talukder
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China. and Department of Physiology and Pharmacology, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Bangladesh
| | - Yu Luo
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
| | - Yue Shen
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
| | - Hao-Ran Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China. and Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China and Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, P. R. China
| |
Collapse
|
|
50
|
Zhu W, Zhang R, Liu S, Tian J, Lv X, Yu F, Xin H. The effect of nanoparticles of cobalt-chromium on human aortic endothelial cells in vitro. J Appl Toxicol 2021; 41:1966-1979. [PMID: 33959985 DOI: 10.1002/jat.4177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/19/2021] [Indexed: 11/08/2022]
Abstract
Despite advances in stent technology for vascular interventions, in-stent restenosis (ISR) remains a main complication. The corrosion of cobalt-chromium (CoCr) alloy coronary stents has been identified to be associated with ISR, whereas its role in ISR has not been elucidated. In the current work, CoCr nanoparticles, simulated corrosion products of CoCr alloy, were used to investigate their effect on the endothelial cells. It has been demonstrated that the cell viability declines and the cell membrane is damaged, indicating the cytotoxicity of CoCr nanoparticles. The expression of GRP78, CHOP, and cleaved-caspase12 proteins has increased when exposed to CoCr nanoparticles, suggesting that CoCr nanoparticles induced cell apoptosis through endoplasmic reticulum (ER) stress-mediated apoptotic pathway. An increased release of adhesion and inflammatory mediators was also induced by CoCr nanoparticles, including ICAM-1, VCAM-1, IL-1β, IL-6, and TNF-α. Our results demonstrated that CoCr nanoparticles could trigger apoptosis, adhesion, and inflammation. These findings indicated potential damaging effects of CoCr nanoparticles on the vascular endothelium, which suggested corrosion of CoCr alloy may promote the progression and development of ISR.
Collapse
Affiliation(s)
- Wenxiu Zhu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China.,Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Rui Zhang
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Song Liu
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Jiawei Tian
- Department of Emergency Internal Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaobing Lv
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Fei Yu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Hui Xin
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| |
Collapse
|