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1
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Gao L, Zheng F, Fu Z, Wang W. Dual-responsive nanoparticles targeting ACE-II senescence for therapeutic mitigation of acute lung injury. J Nanobiotechnology 2025; 23:339. [PMID: 40340852 PMCID: PMC12060536 DOI: 10.1186/s12951-025-03382-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 04/10/2025] [Indexed: 05/10/2025] Open
Abstract
Acute lung injury (ALI) is a life-threatening condition characterized by severe pulmonary dysfunction, with alveolar type II epithelial cell (ACE-II) senescence playing a pivotal role in its progression. In this study, we developed pH/reactive oxygen species (ROS) dual-responsive nanoparticles (GNPsanti-SP-C) for the targeted delivery of Growth Differentiation Factor 15 (GDF15) to counteract ACE-II senescence. These nanoparticles (NPs) effectively activate the AMP-activated protein kinase (AMPK)/Sirtuin 1 (SIRT1) signaling pathway, inducing the mitochondrial unfolded protein response (UPRmt) and reversing senescence-associated cellular dysfunction. GNPsanti-SP-C were systematically engineered and demonstrated robust pH/ROS sensitivity, efficient GDF15 release, and precise ACE-II targeting. In lipopolysaccharide (LPS)-induced ALI mouse model, GNPsanti-SP-C treatment significantly mitigated lung injury, reduced inflammatory responses, and enhanced pulmonary function, as evidenced by decreased inflammatory markers, lung edema, and improved histopathology. Single-cell transcriptomic and proteomic analyses revealed increased ACE-II cell populations, reduced expression of senescence markers, and upregulation of AMPK/SIRT1 signaling. In vitro studies further demonstrated that UPRmt activation is associated with the NPs' therapeutic effects, suggesting a potential role in their mechanism of action. These findings demonstrate the potential of GDF15-loaded dual-responsive NPs as an innovative strategy to address cellular senescence and alleviate ALI-associated pulmonary damage.
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Affiliation(s)
- Linlin Gao
- Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Fushuang Zheng
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zhiling Fu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, Liaoning Province, China.
| | - Wei Wang
- Department of Anesthesiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, Liaoning Province, China.
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2
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Machado IF, Palmeira CM, Rolo AP. Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging. Ageing Res Rev 2025; 109:102762. [PMID: 40320152 DOI: 10.1016/j.arr.2025.102762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 04/09/2025] [Accepted: 04/30/2025] [Indexed: 05/08/2025]
Abstract
Mitochondria supply most of the energy for cellular functions and coordinate numerous cellular pathways. Their dynamic nature allows them to adjust to stress and cellular metabolic demands, thus ensuring the preservation of cellular homeostasis. Loss of normal mitochondrial function compromises cell survival and has been implicated in the development of many diseases and in aging. Although exposure to continuous or severe stress has adverse effects on cells, mild mitochondrial stress enhances mitochondrial function and potentially extends health span through mitochondrial adaptive responses. Over the past few decades, sestrin2 (SESN2) has emerged as a pivotal regulator of stress responses. For instance, SESN2 responds to genotoxic, oxidative, and metabolic stress, promoting cellular defense against stress-associated damage. Here, we focus on recent findings that establish SESN2 as an orchestrator of mitochondrial stress adaptation, which is supported by its involvement in the integrated stress response, mitochondrial biogenesis, and mitophagy. Additionally, we discuss the integral role of SESN2 in mediating the health benefits of exercise as well as its impact on skeletal muscle, liver and heart injury, and aging.
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Affiliation(s)
- Ivo F Machado
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CiBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Institute of Interdisciplinary Research, Doctoral Program in Experimental Biology and Biomedicine (PDBEB), University of Coimbra, Coimbra, Portugal
| | - Carlos M Palmeira
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CiBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | - Anabela P Rolo
- CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CiBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
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3
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Turkel I, Kubat GB, Fatsa T, Acet O, Ozerklig B, Yazgan B, Simsek G, Singh KK, Kosar SN. Acute treadmill exercise induces mitochondrial unfolded protein response in skeletal muscle of male rats. BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2025; 1866:149532. [PMID: 39675514 DOI: 10.1016/j.bbabio.2024.149532] [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: 09/20/2024] [Revised: 11/24/2024] [Accepted: 12/10/2024] [Indexed: 12/17/2024]
Abstract
Mitochondria are often referred to as the energy centers of the cell and are recognized as key players in signal transduction, sensing, and responding to internal and external stimuli. Under stress conditions, the mitochondrial unfolded protein response (UPRmt), a conserved mitochondrial quality control mechanism, is activated to maintain mitochondrial and cellular homeostasis. As a physiological stimulus, exercise-induced mitochondrial perturbations trigger UPRmt, coordinating mitochondria-to-nucleus communication and initiating a transcriptional program to restore mitochondrial function. The aim of this study was to evaluate the UPRmt signaling response to acute exercise in skeletal muscle. Male rats were subjected to acute treadmill exercise at 25 m/min for 60 min on a 0 % grade. Plantaris muscles were collected from both sedentary and exercise groups at various times: immediately (0), and at 1, 3, 6, 12, and 24 h post-exercise. Reactive oxygen species (ROS) production was assessed using hydrogen peroxide assay and dihydroethidium staining. Additionally, the mRNA and protein expression of UPRmt markers were measured using ELISA and real-time PCR. Mitochondrial activity was assessed using succinate dehydrogenase (SDH) and cytochrome c oxidase (COX) staining. Our results demonstrated that acute exercise increased ROS production and upregulated UPRmt markers at both gene and protein levels. Moreover, skeletal muscle exhibited an increase in mitochondrial activity in response to exercise, as indicated by SDH and COX staining. These findings suggest that acute treadmill exercise is sufficient to induce ROS production, activate UPRmt signaling, and enhance mitochondrial activity in skeletal muscle, expanding our understanding of mitochondrial adaptations to exercise.
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Affiliation(s)
- Ibrahim Turkel
- Department of Exercise and Sport Sciences, Faculty of Sport Sciences, Hacettepe University, Ankara, Turkey.
| | - Gokhan Burcin Kubat
- Department of Mitochondria and Cellular Research, Gulhane Health Sciences Institute, University of Health Sciences, Ankara, Turkey; Gulhane Training and Research Hospital, University of Health Sciences, Ankara, Turkey.
| | - Tugba Fatsa
- Gulhane Health Sciences Institute, University of Health Sciences, Ankara, Turkey
| | - Ozgu Acet
- Department of Pathology, Gulhane Training and Research Hospital, Ankara, Turkey
| | - Berkay Ozerklig
- Department of Exercise and Sport Sciences, Faculty of Sport Sciences, Hacettepe University, Ankara, Turkey; Faculty of Kinesiology and Recreation Management, University of Manitoba, Winnipeg, Canada; Children's Hospital Research Institute of Manitoba (CHRIM), Winnipeg, Canada
| | - Burak Yazgan
- Department of Medical Services and Techniques, Sabuncuoglu Serefeddin Health Services Vocational School, Amasya University, Amasya, Turkey
| | - Gulcin Simsek
- Department of Pathology, Gulhane Training and Research Hospital, Ankara, Turkey
| | - Keshav K Singh
- Departments of Genetics, Dermatology and Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sukran Nazan Kosar
- Division of Exercise Nutrition and Metabolism, Faculty of Sport Sciences, Hacettepe University, Ankara, Turkey
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4
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Ganguly U, Carroll T, Nehrke K, Johnson GVW. Mitochondrial Quality Control in Alzheimer's Disease: Insights from Caenorhabditis elegans Models. Antioxidants (Basel) 2024; 13:1343. [PMID: 39594485 PMCID: PMC11590956 DOI: 10.3390/antiox13111343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 10/16/2024] [Accepted: 10/24/2024] [Indexed: 11/28/2024] Open
Abstract
Alzheimer's disease (AD) is a complex neurodegenerative disorder that is classically defined by the extracellular deposition of senile plaques rich in amyloid-beta (Aβ) protein and the intracellular accumulation of neurofibrillary tangles (NFTs) that are rich in aberrantly modified tau protein. In addition to aggregative and proteostatic abnormalities, neurons affected by AD also frequently possess dysfunctional mitochondria and disrupted mitochondrial maintenance, such as the inability to eliminate damaged mitochondria via mitophagy. Decades have been spent interrogating the etiopathogenesis of AD, and contributions from model organism research have aided in developing a more fundamental understanding of molecular dysfunction caused by Aβ and toxic tau aggregates. The soil nematode C. elegans is a genetic model organism that has been widely used for interrogating neurodegenerative mechanisms including AD. In this review, we discuss the advantages and limitations of the many C. elegans AD models, with a special focus and discussion on how mitochondrial quality control pathways (namely mitophagy) may contribute to AD development. We also summarize evidence on how targeting mitophagy has been therapeutically beneficial in AD. Lastly, we delineate possible mechanisms that can work alone or in concert to ultimately lead to mitophagy impairment in neurons and may contribute to AD etiopathology.
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Affiliation(s)
- Upasana Ganguly
- Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center (URMC), Rochester, NY 14642, USA;
| | - Trae Carroll
- Department of Pathology, University of Rochester Medical Center (URMC), Rochester, NY 14642, USA;
| | - Keith Nehrke
- Department of Medicine, Nephrology Division, University of Rochester Medical Center (URMC), Rochester, NY 14642, USA;
| | - Gail V. W. Johnson
- Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center (URMC), Rochester, NY 14642, USA;
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5
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Carneiro FS, Katashima CK, Dodge JD, Cintra DE, Pauli JR, Da Silva ASR, Ropelle ER. Tissue-specific roles of mitochondrial unfolded protein response during obesity. Obes Rev 2024; 25:e13791. [PMID: 38880974 DOI: 10.1111/obr.13791] [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: 09/27/2023] [Revised: 03/20/2024] [Accepted: 06/02/2024] [Indexed: 06/18/2024]
Abstract
Obesity is a worldwide multifactorial disease caused by an imbalance in energy metabolism, increasing adiposity, weight gain, and promoting related diseases such as diabetes, cardiovascular diseases, neurodegeneration, and cancer. Recent findings have reported that metabolic stress related to obesity induces a mitochondrial stress response called mitochondrial unfolded protein response (UPRmt), a quality control pathway that occurs in a nuclear DNA-mitochondria crosstalk, causing transduction of chaperones and proteases under stress conditions. The duality of UPRmt signaling, with both beneficial and detrimental effects, acts in different contexts depending on the tissue, cell type, and physiological states, affecting the mitochondrial function and efficiency and the metabolism homeostasis during obesity, which remains not fully clarified. Therefore, this review discusses the most recent findings regarding UPRmt signaling during obesity, bringing an overview of UPRmt across different metabolic tissues.
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Affiliation(s)
- Fernanda S Carneiro
- Laboratory of Molecular Biology of Exercise (LaBMEx), Faculty of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Carlos K Katashima
- Laboratory of Molecular Biology of Exercise (LaBMEx), Faculty of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Joshua D Dodge
- Department of Biology, The University of Texas at Arlington (UTA), Arlington, Texas, USA
| | - Dennys E Cintra
- Laboratory of Nutritional Genomic, School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - José Rodrigo Pauli
- Laboratory of Molecular Biology of Exercise (LaBMEx), Faculty of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
- Obesity and Comorbidities Research Center (OCRC), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Adelino S R Da Silva
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Eduardo R Ropelle
- Laboratory of Molecular Biology of Exercise (LaBMEx), Faculty of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
- Obesity and Comorbidities Research Center (OCRC), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
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Chen J, Jia S, Guo C, Fan Z, Yan W, Dong K. Research Progress on the Effect and Mechanism of Exercise Intervention on Sarcopenia Obesity. Clin Interv Aging 2024; 19:1407-1422. [PMID: 39139211 PMCID: PMC11319865 DOI: 10.2147/cia.s473083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 08/02/2024] [Indexed: 08/15/2024] Open
Abstract
With the increasingly severe situation of obesity and population aging, there is growing concern about sarcopenia obesity (SO). SO refers to the coexistence of obesity and sarcopenia, which imposes a heavier burden on individuals and society compared to obesity or sarcopenia alone. Therefore, comprehending the pathogenesis of SO and implementing effective clinical interventions are vital for its prevention and treatment. This review uses a comprehensive literature search and analysis of PubMed, Web of Science, and CNKI databases, with search terms including "Sarcopenic obesity", "exercise", "cytokines", "inflammation", "mitochondrial quality control", and "microRNA", covering relevant studies published up to July 2024. The results indicate that the pathogenesis of SO is complex, involving mechanisms like age-related changes in body composition, hormonal alterations, inflammation, mitochondrial dysfunction, and genetic and epigenetic factors. Regarding exercise interventions for SO, aerobic exercise can reduce fat mass, resistance exercise can increase skeletal muscle mass and strength, and combined exercise can achieve both, making it the optimal intervention for SO. The potential mechanisms by which exercise may prevent and treat SO include regulating cytokine secretion, inhibiting inflammatory pathways, improving mitochondrial quality, and mediating microRNA expression. This review emphasizes the effectiveness of exercise interventions in mitigating sarcopenic obesity through comprehensive analysis of its multifactorial pathogenesis and the mechanistic insights into exercise's therapeutic effects. Understanding these mechanisms informs targeted therapeutic strategies aimed at alleviating the societal and individual burdens associated with SO.
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Affiliation(s)
- Jun Chen
- School of Graduate, Wuhan Sport University, Wuhan, 430079, People’s Republic of China
| | - Shaohui Jia
- School of Sports Medicine, Wuhan Sport University, Wuhan, 430079, People’s Republic of China
| | - Chenggen Guo
- School of Sports Training, Wuhan Sport University, Wuhan, 430079, People’s Republic of China
| | - Zhiwei Fan
- School of Graduate, Wuhan Sport University, Wuhan, 430079, People’s Republic of China
| | - Weiyi Yan
- School of Graduate, Wuhan Sport University, Wuhan, 430079, People’s Republic of China
| | - Kunwei Dong
- School of Arts, Wuhan Sport University, Wuhan, 430079, People’s Republic of China
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Deng J, Wang D, Shi Y, Lin L, Gao W, Sun Y, Song X, Li Y, Li J. Mitochondrial unfolded protein response mechanism and its cardiovascular protective effects. Biomed Pharmacother 2024; 177:116989. [PMID: 38959609 DOI: 10.1016/j.biopha.2024.116989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 06/12/2024] [Accepted: 06/15/2024] [Indexed: 07/05/2024] Open
Abstract
The mitochondrial unfolded protein response (UPRmt) is a cytoprotective response in response to cellular stress that is activated in response to mitochondrial stress to maintain intra-protein homeostasis, thereby protecting the cell from a variety of stimuli. The activation of this response has been linked to cardiovascular diseases. Here, we reviewed the current understanding of UPRmt and discussed its specific molecular mechanism, mainly in mammals, as well as addressing its protective role against cardiovascular diseases, so as to provide direction for further research on UPRmt and therapies targeting cardiovascular diseases in the future.
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Affiliation(s)
- Jinlan Deng
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Danyang Wang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yanmei Shi
- Department of Cardiology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lin Lin
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Weihan Gao
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yu Sun
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiayinan Song
- Chinese University of Traditional Chinese Medicine,Beijing University of Chinese Medicine, Chaoyang, China
| | - Yunlun Li
- Department of Cardiology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jie Li
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China.
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8
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Nirmala FS, Lee H, Kim YI, Hahm JH, Seo HD, Kim M, Jung CH, Ahn J. Exercise-induced signaling activation by Chrysanthemum zawadskii and its active compound, linarin, ameliorates age-related sarcopenia through Sestrin 1 regulation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155695. [PMID: 38728922 DOI: 10.1016/j.phymed.2024.155695] [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: 01/14/2024] [Revised: 04/17/2024] [Accepted: 04/29/2024] [Indexed: 05/12/2024]
Abstract
BACKGROUND Exercise is an effective strategy to prevent sarcopenia, but high physical inactivity in the elderly requires alternative therapeutic approaches. Exercise mimetics are therapeutic compounds that simulate the beneficial effects of exercise on skeletal muscles. However, the toxicity and adverse effects of exercise mimetics raise serious concerns. PURPOSE We aimed to search novel plant-based alternatives to activate exercise induced-signaling. METHODS We used open databases and luciferase assays to identify plant-derived alternatives to activate exercise-induced signaling and compared its efficacy to mild intensity continuous training (MICT) in aged C57BL/6 mice. The nineteen-month-old mice were either fed an experimental diet supplemented with the isolated alternative or subjected to MICT for up to 21 mo of age. RESULTS Our analysis revealed that Chrysanthemum zawadskii Herbich var latillobum (Maxim.) Kitamura (CZH), a medicinal plant rich in linarin, is a novel activator of peroxisome proliferator-activated receptor δ (PPARδ) and estrogen-related receptor γ (ERRγ), key regulators of exercise-induced positive effects on muscles. CZH supplementation ameliorated the loss of muscle function and mass, and increased PPARδ and ERRγ expression in mouse muscles. CZH also improved mitochondrial functions and proteostasis in aged mice, similar to MICT. Furthermore, CZH and linarin induced the activation of Sestrin 1, a key mediator of exercise benefits, in muscle. Silencing Sestrin 1 negated the increase in myogenesis and mitochondrial respiration by CZH and linarin in primary myoblasts from old mice. CONCLUSION Our findings suggest the potential of CZH as a novel plant-derived alternative to activate exercise-induced signaling for preventing sarcopenia in sedentary older adults. This could offer a safer therapeutic option for sarcopenia treatment.
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Affiliation(s)
- Farida S Nirmala
- Department of Food Biotechnology, University of Science and Technology, Daejeon, South Korea; Research Group of Aging and Metabolism, Korea Food Research Institute, Wanju-gun, South Korea
| | - Hyunjung Lee
- Research Group of Aging and Metabolism, Korea Food Research Institute, Wanju-gun, South Korea
| | - Young-In Kim
- Research Group of Aging and Metabolism, Korea Food Research Institute, Wanju-gun, South Korea
| | - Jeong-Hoon Hahm
- Research Group of Aging and Metabolism, Korea Food Research Institute, Wanju-gun, South Korea
| | - Hyo-Deok Seo
- Research Group of Aging and Metabolism, Korea Food Research Institute, Wanju-gun, South Korea
| | - Minjung Kim
- Research Group of Personalized Diet, Korea Food Research Institute, Wanju-gun, South Korea
| | - Chang Hwa Jung
- Department of Food Biotechnology, University of Science and Technology, Daejeon, South Korea; Research Group of Aging and Metabolism, Korea Food Research Institute, Wanju-gun, South Korea
| | - Jiyun Ahn
- Department of Food Biotechnology, University of Science and Technology, Daejeon, South Korea; Research Group of Aging and Metabolism, Korea Food Research Institute, Wanju-gun, South Korea.
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Hahm JH, Nirmala FS, Ha TY, Ahn J. Nutritional approaches targeting mitochondria for the prevention of sarcopenia. Nutr Rev 2024; 82:676-694. [PMID: 37475189 DOI: 10.1093/nutrit/nuad084] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/22/2023] Open
Abstract
A decline in function and loss of mass, a condition known as sarcopenia, is observed in the skeletal muscles with aging. Sarcopenia has a negative effect on the quality of life of elderly. Individuals with sarcopenia are at particular risk for adverse outcomes, such as reduced mobility, fall-related injuries, and type 2 diabetes mellitus. Although the pathogenesis of sarcopenia is multifaceted, mitochondrial dysfunction is regarded as a major contributor for muscle aging. Hence, the development of preventive and therapeutic strategies to improve mitochondrial function during aging is imperative for sarcopenia treatment. However, effective and specific drugs that can be used for the treatment are not yet approved. Instead studies on the relationship between food intake and muscle aging have suggested that nutritional intake or dietary control could be an alternative approach for the amelioration of muscle aging. This narrative review approaches various nutritional components and diets as a treatment for sarcopenia by modulating mitochondrial homeostasis and improving mitochondria. Age-related changes in mitochondrial function and the molecular mechanisms that help improve mitochondrial homeostasis are discussed, and the nutritional components and diet that modulate these molecular mechanisms are addressed.
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Affiliation(s)
- Jeong-Hoon Hahm
- Research Group of Aging and Metabolism, Korea Food Research Institute, Wanju-gun, South Korea
| | - Farida S Nirmala
- Research Group of Aging and Metabolism, Korea Food Research Institute, Wanju-gun, South Korea
- Department of Food Biotechnology, Korea University of Science and Technology, Daejeon-si, South Korea
| | - Tae Youl Ha
- Research Group of Aging and Metabolism, Korea Food Research Institute, Wanju-gun, South Korea
- Department of Food Biotechnology, Korea University of Science and Technology, Daejeon-si, South Korea
| | - Jiyun Ahn
- Research Group of Aging and Metabolism, Korea Food Research Institute, Wanju-gun, South Korea
- Department of Food Biotechnology, Korea University of Science and Technology, Daejeon-si, South Korea
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Yan X, Fu P, Zhang Y, Ling D, Reynolds L, Hua W, Wang Z, Ma F, Li B, Yu J, Liu Y, Gong L, Zhang E. MCC950 Ameliorates Diabetic Muscle Atrophy in Mice by Inhibition of Pyroptosis and Its Synergistic Effect with Aerobic Exercise. Molecules 2024; 29:712. [PMID: 38338456 PMCID: PMC10856337 DOI: 10.3390/molecules29030712] [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: 12/22/2023] [Revised: 01/17/2024] [Accepted: 02/01/2024] [Indexed: 02/12/2024] Open
Abstract
Diabetic muscle atrophy is an inflammation-related complication of type-2 diabetes mellitus (T2DM). Even though regular exercise prevents further deterioration of atrophic status, there is no effective mediator available for treatment and the underlying cellular mechanisms are less explored. In this study, we investigated the therapeutic potential of MCC950, a specific, small-molecule inhibitor of NLRP3, to treat pyroptosis and diabetic muscle atrophy in mice. Furthermore, we used MCC950 to intervene in the protective effects of aerobic exercise against muscle atrophy in diabetic mice. Blood and gastrocnemius muscle (GAS) samples were collected after 12 weeks of intervention and the atrophic state was assessed. We initially corroborated a diabetic muscle atrophy phenotype in db/db mice (D) by comparison with control m/m mice (W) by examining parameters such as fasting blood glucose (D vs. W: 24.47 ± 0.45 mmol L-1 vs. 4.26 ± 0.6 mmol L-1, p < 0.05), grip strength (D vs. W: 166.87 ± 15.19 g vs. 191.76 ± 14.13 g, p < 0.05), exercise time (D vs. W: 1082.38 ± 104.67 s vs. 1716 ± 168.55 s, p < 0.05) and exercise speed to exhaustion (D vs. W: 24.25 ± 2.12 m min-1 vs. 34.75 ± 2.66 m min-1, p < 0.05), GAS wet weight (D vs. W: 0.07 ± 0.01 g vs. 0.13 ± 0.01 g, p < 0.05), the ratio of GAS wet weight to body weight (D vs. W: 0.18 ± 0.01% vs. 0.54 ± 0.02%, p < 0.05), and muscle fiber cross-sectional area (FCSA) (D vs. W: 1875 ± 368.19 µm2 vs. 2747.83 ± 406.44 µm2, p < 0.05). We found that both MCC950 (10 mg kg-1) treatment and exercise improved the atrophic parameters that had deteriorated in the db/db mice, inhibited serum inflammatory markers and significantly attenuated pyroptosis in atrophic GAS. In addition, a combined MCC950 treatment with exercise (DEI) exhibited a further improvement in glucose uptake capacity and muscle performance. This combined treatment also improved the FCSA of GAS muscle indicated by Laminin immunofluorescence compared to the group with the inhibitor treatment alone (DI) (DEI vs. DI: 2597 ± 310.97 vs. 1974.67 ± 326.15 µm2, p < 0.05) or exercise only (DE) (DEI vs. DE: 2597 ± 310.97 vs. 2006.33 ± 263.468 µm2, p < 0.05). Intriguingly, the combination of MCC950 treatment and exercise significantly reduced NLRP3-mediated inflammatory factors such as cleaved-Caspase-1, GSDMD-N and prevented apoptosis and pyroptosis in atrophic GAS. These findings for the first time demonstrate that targeting NLRP3-mediated pyroptosis with MCC950 improves diabetic muscle homeostasis and muscle function. We also report that inhibiting pyroptosis by MCC950 can enhance the beneficial effects of aerobic exercise on diabetic muscle atrophy. Since T2DM and muscle atrophy are age-related diseases, the young mice used in the current study do not seem to fully reflect the characteristics of diabetic muscle atrophy. Considering the fragile nature of db/db mice and for the complete implementation of the exercise intervention, we used relatively young db/db mice and the atrophic state in the mice was thoroughly confirmed. Taken together, the current study comprehensively investigated the therapeutic effect of NLRP3-mediated pyroptosis inhibited by MCC950 on diabetic muscle mass, strength and exercise performance, as well as the synergistic effects of MCC950 and exercise intervention, therefore providing a novel strategy for the treatment of the disease.
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Affiliation(s)
- Xiaoyu Yan
- Key Laboratory of Exercise and Physical Fitness of Ministry of Education, Beijing Sport University, Beijing 100084, China; (X.Y.); (J.Y.)
- School of Sport Science, Beijing Sport University, Beijing 100084, China; (P.F.); (D.L.); (W.H.); (Z.W.); (F.M.); (B.L.); (Y.L.)
| | - Pengyu Fu
- School of Sport Science, Beijing Sport University, Beijing 100084, China; (P.F.); (D.L.); (W.H.); (Z.W.); (F.M.); (B.L.); (Y.L.)
- Department of Physical Education, Northwestern Polytechnical University, Xi’an 710072, China
| | - Yimin Zhang
- Key Laboratory of Exercise and Physical Fitness of Ministry of Education, Beijing Sport University, Beijing 100084, China; (X.Y.); (J.Y.)
- School of Sport Science, Beijing Sport University, Beijing 100084, China; (P.F.); (D.L.); (W.H.); (Z.W.); (F.M.); (B.L.); (Y.L.)
| | - Dongmei Ling
- School of Sport Science, Beijing Sport University, Beijing 100084, China; (P.F.); (D.L.); (W.H.); (Z.W.); (F.M.); (B.L.); (Y.L.)
| | - Lewis Reynolds
- Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Lund University, 21428 Malmö, Sweden (E.Z.)
- NanoLund Center for NanoScience, Lund University, 22100 Lund, Sweden
| | - Weicheng Hua
- School of Sport Science, Beijing Sport University, Beijing 100084, China; (P.F.); (D.L.); (W.H.); (Z.W.); (F.M.); (B.L.); (Y.L.)
| | - Zhiyuan Wang
- School of Sport Science, Beijing Sport University, Beijing 100084, China; (P.F.); (D.L.); (W.H.); (Z.W.); (F.M.); (B.L.); (Y.L.)
| | - Fangyuan Ma
- School of Sport Science, Beijing Sport University, Beijing 100084, China; (P.F.); (D.L.); (W.H.); (Z.W.); (F.M.); (B.L.); (Y.L.)
- School of Life Sciences, Nankai University, Tianjin 300071, China
| | - Boxuan Li
- School of Sport Science, Beijing Sport University, Beijing 100084, China; (P.F.); (D.L.); (W.H.); (Z.W.); (F.M.); (B.L.); (Y.L.)
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
| | - Jingjing Yu
- Key Laboratory of Exercise and Physical Fitness of Ministry of Education, Beijing Sport University, Beijing 100084, China; (X.Y.); (J.Y.)
| | - Yujia Liu
- School of Sport Science, Beijing Sport University, Beijing 100084, China; (P.F.); (D.L.); (W.H.); (Z.W.); (F.M.); (B.L.); (Y.L.)
- Institute of Physical Education, Jiangsu Normal University, Xuzhou 221116, China
| | - Lijing Gong
- Key Laboratory of Exercise and Physical Fitness of Ministry of Education, Beijing Sport University, Beijing 100084, China; (X.Y.); (J.Y.)
| | - Enming Zhang
- Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Lund University, 21428 Malmö, Sweden (E.Z.)
- NanoLund Center for NanoScience, Lund University, 22100 Lund, Sweden
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11
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Shi L, Tan Y, Zheng W, Cao G, Zhou H, Li P, Cui J, Song Y, Feng L, Li H, Shan W, Zhang B, Yi W. CTRP3 alleviates mitochondrial dysfunction and oxidative stress injury in pathological cardiac hypertrophy by activating UPRmt via the SIRT1/ATF5 axis. Cell Death Discov 2024; 10:53. [PMID: 38278820 PMCID: PMC10817931 DOI: 10.1038/s41420-024-01813-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 12/20/2023] [Accepted: 01/09/2024] [Indexed: 01/28/2024] Open
Abstract
Pathological cardiac hypertrophy is an independent risk factor for heart failure. Disruption of mitochondrial protein homeostasis plays a key role in pathological cardiac hypertrophy; however, the mechanism of maintaining mitochondrial homeostasis in pathological cardiac hypertrophy remains unclear. In this study, we investigated the regulatory mechanisms of mitochondrial protein homeostasis in pathological cardiac hypertrophy. Wildtype (WT) mice, knockout mice, and mice transfected with lentivirus overexpressing mouse C1q-tumor necrosis factor-related protein-3 (CTRP3) underwent transverse aortic constriction or sham surgery. After 4 weeks, cardiac function, mitochondrial function, and oxidative stress injury were examined. For mechanistic studies, neonatal rat cardiomyocytes were treated with small interfering RNA or overexpression plasmids for the relevant genes. CTRP3 overexpression attenuated transverse aortic constriction (TAC) induced pathological cardiac hypertrophy, mitochondrial dysfunction, and oxidative stress injury compared to that in WT mice. TAC or Ang II resulted in compensatory activation of UPRmt, but this was not sufficient to counteract pathologic cardiac hypertrophy. CTRP3 overexpression further induced activation of UPRmt during pathologic cardiac hypertrophy and thereby alleviated pathologic cardiac hypertrophy, whereas CTRP3 knockout or knockdown inhibited UPRmt. ATF5 was a key regulatory molecule of UPRmt, as ATF5 knockout prevented the cardioprotective effect of CTRP3 in TAC mice. In vitro, SIRT1 was identified as a possible downstream CTRP3 effector molecule, and SIRT1 knockout blocked the cardioprotective effects of CTRP3. Our results also suggest that ATF5 may be regulated by SIRT1. Our study demonstrates that CTRP3 activates UPRmt via the SIRT1/ATF5 axis under pathological myocardial hypertrophy, thus attenuating mitochondrial dysfunction and oxidative stress injury.
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Affiliation(s)
- Lei Shi
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Yanzhen Tan
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Wenying Zheng
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Guojie Cao
- Department of General Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Haitao Zhou
- Department of General Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Panpan Li
- Department of General Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Jun Cui
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Yujie Song
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Lele Feng
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Hong Li
- Department of General Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Wenju Shan
- Department of General Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Bing Zhang
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Wei Yi
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
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12
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Zhao Y, Li C, Zhou S, He Y, Wang Y, Zhang Y, Wen L. Enhanced glucose utilization of skeletal muscle after 4 weeks of intermittent hypoxia in a mouse model of type 2 diabetes. PLoS One 2024; 19:e0296815. [PMID: 38271325 PMCID: PMC10810429 DOI: 10.1371/journal.pone.0296815] [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: 08/12/2023] [Accepted: 12/19/2023] [Indexed: 01/27/2024] Open
Abstract
BACKGROUND Intermittent hypoxia intervention (IHI) has been shown to reduces blood glucose and improves insulin resistance in type 2 diabetes (T2D) and has been suggested as a complementary or alternative intervention to exercise for individuals with limited mobility. Previous research on IHI has assessed cellular glucose uptake rather than utilization. The purpose of this study was to determine the effect of a 4-week IHI, with or without an aerobic exercise, on skeletal muscle glucose utilization as indicated by the changes in pyruvate, lactate, NAD+, and NADH, using a mouse model of diet-induced T2D. In addition, the effects of one exposure to hypoxia (acute) and of a 4-week IHI (chronic) were compared to explore their relationship. METHODS C57BL/6J mice were randomly assigned to normal control and high-fat-diet groups, and the mice that developed diet-induced diabetes were assigned to diabetes control, and intervention groups with 1 hour (acute) or 4 weeks (1 hour/day, 6 days/week) exposure to a hypoxic envrionment (0.15 FiO2), exercise (treadmill run) in normoxia, and exercise in hypoxia, respectively, with N = 7 in each group. The effects of the interventions on concentrations of fasting blood glucose, muscle glucose, GLUT4, lactate, pyruvate, nicotinamide adenine dinucleotide (NAD+), and NADH were measured, and statistically compared between the groups. RESULTS Compared with diabetes control group, the mice treated in the hypoxic environment for 4 weeks showed a significantly higher pyruvate levels and lower lactate/pyruvate ratios in the quadriceps muscle, and the mice exposed to hypoxia without or with aerobic exercise for either for 4 weeks or just 1 hour showed higher NAD+ levels and lower NADH/NAD+ ratios. CONCLUSIONS Exposure to moderate hypoxia for either one bout or 4 weeks significantly increased the body's mitochondrial NAD cyclethe in diabetic mice even in the absence of aerobic exercise. The hypoxia and exercise interventions exhibited synergistic effects on glycolysis. These findings provide mechanistic insights into the effects of IHI in respect of the management of hyperglycemia.
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Affiliation(s)
- Yuqi Zhao
- School of Social Sports and Health Sciences, Tianjin University of Sport, Tianjin, China
- School of Exercise and Health, Nanjing Sport Institute, Nanjing, Jiangsu, China
| | - Chaoqun Li
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Shi Zhou
- Faculty of Health, Southern Cross University, Lismore, Australia
| | - Youyu He
- School of Social Sports and Health Sciences, Tianjin University of Sport, Tianjin, China
| | - Yun Wang
- Faculty of Health, Southern Cross University, Lismore, Australia
| | - Yuan Zhang
- Faculty of Health, Southern Cross University, Lismore, Australia
| | - Li Wen
- School of Social Sports and Health Sciences, Tianjin University of Sport, Tianjin, China
- School of Exercise and Health, Nanjing Sport Institute, Nanjing, Jiangsu, China
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13
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Gaspar RS, Katashima CK, Crisol BM, Carneiro FS, Sampaio I, Silveira LDR, Silva ASRD, Cintra DE, Pauli JR, Ropelle ER. Physical exercise elicits UPR mt in the skeletal muscle: The role of c-Jun N-terminal kinase. Mol Metab 2023; 78:101816. [PMID: 37821006 PMCID: PMC10590869 DOI: 10.1016/j.molmet.2023.101816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 08/10/2023] [Accepted: 10/02/2023] [Indexed: 10/13/2023] Open
Abstract
OBJECTIVE The mitochondrial unfolded protein response (UPRmt) is an adaptive cellular response to stress to ensure mitochondrial proteostasis and function. Here we explore the capacity of physical exercise to induce UPRmt in the skeletal muscle. METHODS Therefore, we combined mouse models of exercise (swimming and treadmill running), pharmacological intervention, and bioinformatics analyses. RESULTS Firstly, RNA sequencing and Western blotting analysis revealed that an acute aerobic session stimulated several mitostress-related genes and protein content in muscle, including the UPRmt markers. Conversely, using a large panel of isogenic strains of BXD mice, we identified that BXD73a and 73b strains displayed low levels of several UPRmt-related genes in the skeletal muscle, and this genotypic feature was accompanied by body weight gain, lower locomotor activity, and aerobic capacity. Finally, we identified that c-Jun N-terminal kinase (JNK) activation was critical in exercise-induced UPRmt in the skeletal muscle since pharmacological JNK pathway inhibition blunted exercise-induced UPRmt markers in mice muscle. CONCLUSION Our findings provide new insights into how exercise triggers mitostress signals toward the oxidative capacity in the skeletal muscle.
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Affiliation(s)
- Rodrigo Stellzer Gaspar
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences (FCA), University of Campinas (Unicamp), Limeira, Brazil; Laboratory of Cell Signaling, Obesity and Comorbidities Research Center (OCRC), University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Carlos Kiyoshi Katashima
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences (FCA), University of Campinas (Unicamp), Limeira, Brazil
| | - Barbara Moreira Crisol
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences (FCA), University of Campinas (Unicamp), Limeira, Brazil
| | - Fernanda Silva Carneiro
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences (FCA), University of Campinas (Unicamp), Limeira, Brazil
| | - Igor Sampaio
- Department of Structural and Functional Biology, Biology Institute, University of Campinas (Unicamp), Campinas, Brazil
| | - Leonardo Dos Reis Silveira
- Department of Structural and Functional Biology, Biology Institute, University of Campinas (Unicamp), Campinas, Brazil
| | - Adelino Sanchez Ramos da Silva
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Dennys Esper Cintra
- Laboratory of Nutritional Genomics (Labgen), School of Applied Sciences (FCA), University of Campinas (Unicamp), Limeira, Brazil
| | - José Rodrigo Pauli
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences (FCA), University of Campinas (Unicamp), Limeira, Brazil
| | - Eduardo Rochete Ropelle
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences (FCA), University of Campinas (Unicamp), Limeira, Brazil; Faculty of Medical Sciences, Department of Internal Medicine. University of Campinas (Unicamp), Campinas, São Paulo, Brazil.
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14
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Mitochondrial protein import and UPR mt in skeletal muscle remodeling and adaptation. Semin Cell Dev Biol 2023; 143:28-36. [PMID: 35063351 DOI: 10.1016/j.semcdb.2022.01.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 12/20/2021] [Accepted: 01/04/2022] [Indexed: 01/03/2023]
Abstract
The biogenesis of mitochondria requires the coordinated expression of the nuclear and the mitochondrial genomes. However, the vast majority of gene products within the organelle are encoded in the nucleus, synthesized in the cytosol, and imported into mitochondria via the protein import machinery, which permit the entry of proteins to expand the mitochondrial network. Once inside, proteins undergo a maturation and folding process brought about by enzymes comprising the unfolded protein response (UPRmt). Protein import and UPRmt activity must be synchronized and matched with mtDNA-encoded subunit synthesis for proper assembly of electron transport chain complexes to avoid proteotoxicity. This review discusses the functions of the import and UPRmt systems in mammalian skeletal muscle, as well as how exercise alters the equilibrium of these pathways in a time-dependent manner, leading to a new steady state of mitochondrial content resulting in enhanced oxidative capacity and improved muscle health.
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15
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Li J, Xu Y, Liu T, Xu Y, Zhao X, Wei J. The Role of Exercise in Maintaining Mitochondrial Proteostasis in Parkinson's Disease. Int J Mol Sci 2023; 24:ijms24097994. [PMID: 37175699 PMCID: PMC10179072 DOI: 10.3390/ijms24097994] [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: 03/27/2023] [Revised: 04/21/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Parkinson's disease (PD) is the second most common rapidly progressive neurodegenerative disease and has serious health and socio-economic consequences. Mitochondrial dysfunction is closely related to the onset and progression of PD, and the use of mitochondria as a target for PD therapy has been gaining traction in terms of both recognition and application. The disruption of mitochondrial proteostasis in the brain tissue of PD patients leads to mitochondrial dysfunction, which manifests as mitochondrial unfolded protein response, mitophagy, and mitochondrial oxidative phosphorylation. Physical exercise is important for the maintenance of human health, and has the great advantage of being a non-pharmacological therapy that is non-toxic, low-cost, and universally applicable. In this review, we investigate the relationships between exercise, mitochondrial proteostasis, and PD and explore the role and mechanisms of mitochondrial proteostasis in delaying PD through exercise.
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Affiliation(s)
- Jingwen Li
- Department of Kinesiology, School of Physical Education, Henan University, Kaifeng 475000, China
- Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Yanli Xu
- Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Tingting Liu
- Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Yuxiang Xu
- Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Xiantao Zhao
- Department of Kinesiology, School of Physical Education, Henan University, Kaifeng 475000, China
- Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Jianshe Wei
- Department of Kinesiology, School of Physical Education, Henan University, Kaifeng 475000, China
- Institute for Brain Sciences Research, School of Life Sciences, Henan University, Kaifeng 475004, China
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16
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Wang Y, Li J, Zhang Z, Wang R, Bo H, Zhang Y. Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle. Life (Basel) 2023; 13:life13041006. [PMID: 37109535 PMCID: PMC10142204 DOI: 10.3390/life13041006] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/09/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023] Open
Abstract
The mitochondrial unfolded protein response (UPRmt) and mitophagy are two mitochondrial quality control (MQC) systems that work at the molecular and organelle levels, respectively, to maintain mitochondrial homeostasis. Under stress conditions, these two processes are simultaneously activated and compensate for each other when one process is insufficient, indicating mechanistic coordination between the UPRmt and mitophagy that is likely controlled by common upstream signals. This review focuses on the molecular signals regulating this coordination and presents evidence showing that this coordination mechanism is impaired during aging and promoted by exercise. Furthermore, the bidirectional regulation of reactive oxygen species (ROS) and AMPK in modulating this mechanism is discussed. The hierarchical surveillance network of MQC can be targeted by exercise-derived ROS to attenuate aging, which offers a molecular basis for potential therapeutic interventions for sarcopenia.
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Affiliation(s)
- Yan Wang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, School of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China
- School of Physical Education, Guangdong Institute of Petrochemical Technology, Maoming 525000, China
| | - Jialin Li
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, School of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China
| | - Ziyi Zhang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, School of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China
| | - Runzi Wang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, School of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China
| | - Hai Bo
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, School of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China
- Department of Military Training Medicines, Logistics University of Chinese People's Armed Police Force, Tianjin 300162, China
| | - Yong Zhang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, School of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China
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17
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Muñoz VR, Botezelli JD, Gaspar RC, da Rocha AL, Vieira RFL, Crisol BM, Braga RR, Severino MB, Nakandakari SCBR, Antunes GC, Brunetto SQ, Ramos CD, Velloso LA, Simabuco FM, de Moura LP, da Silva ASR, Ropelle ER, Cintra DE, Pauli JR. Effects of short-term endurance and strength exercise in the molecular regulation of skeletal muscle in hyperinsulinemic and hyperglycemic Slc2a4 +/- mice. Cell Mol Life Sci 2023; 80:122. [PMID: 37052684 PMCID: PMC11072257 DOI: 10.1007/s00018-023-04771-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 03/08/2023] [Accepted: 03/28/2023] [Indexed: 04/14/2023]
Abstract
OBJECTIVE Intriguingly, hyperinsulinemia, and hyperglycemia can predispose insulin resistance, obesity, and type 2 diabetes, leading to metabolic disturbances. Conversely, physical exercise stimulates skeletal muscle glucose uptake, improving whole-body glucose homeostasis. Therefore, we investigated the impact of short-term physical activity in a mouse model (Slc2a4+/-) that spontaneously develops hyperinsulinemia and hyperglycemia even when fed on a chow diet. METHODS Slc2a4+/- mice were used, that performed 5 days of endurance or strength exercise training. Further analysis included physiological tests (GTT and ITT), skeletal muscle glucose uptake, skeletal muscle RNA-sequencing, mitochondrial function, and experiments with C2C12 cell line. RESULTS When Slc2a4+/- mice were submitted to the endurance or strength training protocol, improvements were observed in the skeletal muscle glucose uptake and glucose metabolism, associated with broad transcriptomic modulation, that was, in part, related to mitochondrial adaptations. The endurance training, but not the strength protocol, was effective in improving skeletal muscle mitochondrial activity and unfolded protein response markers (UPRmt). Moreover, experiments with C2C12 cells indicated that insulin or glucose levels could contribute to these mitochondrial adaptations in skeletal muscle. CONCLUSIONS Both short-term exercise protocols were efficient in whole-body glucose homeostasis and insulin resistance. While endurance exercise plays an important role in transcriptome and mitochondrial activity, strength exercise mostly affects post-translational mechanisms and protein synthesis in skeletal muscle. Thus, the performance of both types of physical exercise proved to be a very effective way to mitigate the impacts of hyperglycemia and hyperinsulinemia in the Slc2a4+/- mouse model.
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Affiliation(s)
- Vitor Rosetto Muñoz
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil.
| | - José Diego Botezelli
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Rafael Calais Gaspar
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Alisson L da Rocha
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Renan Fudoli Lins Vieira
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Barbara Moreira Crisol
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Renata Rosseto Braga
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Matheus Brandemarte Severino
- Multidisciplinary Laboratory of Food and Health (LabMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | | | - Gabriel Calheiros Antunes
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Sérgio Q Brunetto
- Biomedical Engineering Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Celso D Ramos
- Biomedical Engineering Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Department of Radiology, University of Campinas, Campinas, São Paulo, 13084-970, Brazil
| | - Lício Augusto Velloso
- OCRC - Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Laboratory of Cell Signaling, Department of Internal Medicine, University of Campinas, Campinas, São Paulo, 13084-970, Brazil
| | - Fernando Moreira Simabuco
- Multidisciplinary Laboratory of Food and Health (LabMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Leandro Pereira de Moura
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
- OCRC - Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Adelino Sanchez Ramos da Silva
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão, Preto Medical School, University of São Paulo (USP), School of Physical Education and Sport of Ribeirão Preto , Ribeirão Preto, São Paulo, Brazil
| | - Eduardo Rochete Ropelle
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
- OCRC - Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- National Institute of Science and Technology of Obesity and Diabetes, University of Campinas (UNICAMP), Campinas , São Paulo, Brazil
| | - Dennys Esper Cintra
- Laboratory of Nutritional Genomics, University of Campinas (UNICAMP), Limeira,, São Paulo, Brazil
- OCRC - Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - José Rodrigo Pauli
- Laboratory of Molecular Biology of Exercise, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil.
- OCRC - Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
- National Institute of Science and Technology of Obesity and Diabetes, University of Campinas (UNICAMP), Campinas , São Paulo, Brazil.
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18
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Goh J, Wong E, Soh J, Maier AB, Kennedy BK. Targeting the molecular & cellular pillars of human aging with exercise. FEBS J 2023; 290:649-668. [PMID: 34968001 DOI: 10.1111/febs.16337] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 10/29/2021] [Accepted: 12/29/2021] [Indexed: 02/04/2023]
Abstract
Biological aging is the main driver of age-associated chronic diseases. In 2014, the United States National Institute of Aging (NIA) sponsored a meeting between several investigators in the field of aging biology, who identified seven biological pillars of aging and a consensus review, "Geroscience: Linking Aging to Chronic Disease," was published. The pillars of aging demonstrated the conservation of aging pathways in diverse model organisms and thus represent a useful framework with which to study human aging. In this present review, we revisit the seven pillars of aging from the perspective of exercise and discuss how regular physical exercise can modulate these pillars to stave off age-related chronic diseases and maintain functional capacity.
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Affiliation(s)
- Jorming Goh
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Centre for Healthy Longevity, National University Health System (NUHS), Singapore
| | - Esther Wong
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Centre for Healthy Longevity, National University Health System (NUHS), Singapore
| | - Janjira Soh
- Centre for Healthy Longevity, National University Health System (NUHS), Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore
| | - Andrea Britta Maier
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Centre for Healthy Longevity, National University Health System (NUHS), Singapore.,Department of Medicine, National University of Singapore, Singapore.,Department of Medicine and Aged Care, @AgeMelbourne, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Australia.,Department of Human Movement Sciences, @AgeAmsterdam, Amsterdam Movement Sciences, Vrije Universiteit, Amsterdam, The Netherlands
| | - Brian Keith Kennedy
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Centre for Healthy Longevity, National University Health System (NUHS), Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore
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19
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ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle. Mol Metab 2022; 66:101623. [PMID: 36332794 PMCID: PMC9661517 DOI: 10.1016/j.molmet.2022.101623] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 10/19/2022] [Accepted: 10/24/2022] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVES The Mitochondrial Unfolded Protein Response (UPRmt) is a compartment-specific mitochondrial quality control (MQC) mechanism that uses the transcription factor ATF5 to induce the expression of protective enzymes to restore mitochondrial function. Acute exercise is a stressor that has the potential to temporarily disrupt organellar protein homeostasis, however, the roles of ATF5 and the UPRmt in maintaining basal mitochondrial content, function and exercise-induced MQC mechanisms in skeletal muscle are not known. METHODS ATF5 KO and WT mice were examined at rest or after a bout of acute endurance exercise. We measured protein content in whole muscle, nuclear, cytosolic and mitochondrial fractions, in addition to mRNA transcript levels in whole muscle. Using isolated mitochondria, we quantified rates of oxygen consumption and ROS emission to observe the effects of the absence of ATF5 on organelle function. RESULTS ATF5 KO mice exhibited a larger and less functional muscle mitochondrial pool, most likely a culmination of enhanced biogenesis via increased PGC-1α expression, and attenuated mitophagy. The absence of ATF5 resulted in a reduction in antioxidant proteins and increases in mitochondrial ROS emission, cytosolic cytochrome c, and the expression of mitochondrial chaperones. KO muscle also displayed enhanced exercise-induced stress kinase signaling, but a blunted mitophagic and UPRmt gene expression response, complemented by significant increases in the basal mRNA abundance and nuclear localization of ATF4. Instead of promoting its nuclear translocation, acute exercise caused the enrichment of ATF5 in mitochondrial fractions. We also identified PGC-1α as an additional regulator of the basal expression of UPRmt genes. CONCLUSION The transcription factor ATF5 retains a critical role in the maintenance of mitochondrial homeostasis and the appropriate response of muscle to acute exercise for the optimization of mitochondrial quality control.
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20
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Savu DI, Moisoi N. Mitochondria - Nucleus communication in neurodegenerative disease. Who talks first, who talks louder? BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2022; 1863:148588. [PMID: 35780856 DOI: 10.1016/j.bbabio.2022.148588] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 06/09/2022] [Accepted: 06/24/2022] [Indexed: 06/15/2023]
Abstract
Mitochondria - nuclear coadaptation has been central to eukaryotic evolution. The dynamic dialogue between the two compartments within the context of multiorganellar interactions is critical for maintaining cellular homeostasis and directing the balance survival-death in case of cellular stress. The conceptualisation of mitochondria - nucleus communication has so far been focused on the communication from the mitochondria under stress to the nucleus and the consequent signalling responses, as well as from the nucleus to mitochondria in the context of DNA damage and repair. During ageing processes this dialogue may be better viewed as an integrated bidirectional 'talk' with feedback loops that expand beyond these two organelles depending on physiological cues. Here we explore the current views on mitochondria - nucleus dialogue and its role in maintaining cellular health with a focus on brain cells and neurodegenerative disease. Thus, we detail the transcriptional responses initiated by mitochondrial dysfunction in order to protect itself and the general cellular homeostasis. Additionally, we are reviewing the knowledge of the stress pathways initiated by DNA damage which affect mitochondria homeostasis and we add the information provided by the study of combined mitochondrial and genotoxic damage. Finally, we reflect on how each organelle may take the lead in this dialogue in an ageing context where both compartments undergo accumulation of stress and damage and where, perhaps, even the communications' mechanisms may suffer interruptions.
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Affiliation(s)
- Diana Iulia Savu
- Department of Life and Environmental Physics, Horia Hulubei National Institute of Physics and Nuclear Engineering, Reactorului 30, P.O. Box MG-6, Magurele 077125, Romania
| | - Nicoleta Moisoi
- Leicester School of Pharmacy, Leicester Institute for Pharmaceutical Innovation, Faculty of Health Sciences, De Montfort University, The Gateway, Hawthorn Building 1.03, LE1 9BH Leicester, UK.
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21
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He Y, Ding Q, Chen W, Lin C, Ge L, Ying C, Xu K, Wu Z, Xu L, Ran J, Chen W, Wu L. LONP1 downregulation with ageing contributes to osteoarthritis via mitochondrial dysfunction. Free Radic Biol Med 2022; 191:176-190. [PMID: 36064070 DOI: 10.1016/j.freeradbiomed.2022.08.038] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/18/2022] [Accepted: 08/29/2022] [Indexed: 12/12/2022]
Abstract
Osteoarthritis (OA) is an age-related disorder and an important cause of disability that is characterized by a senescence-associated secretory phenotype and matrix degradation leading to a gradual loss of articular cartilage integrity. Mitochondria, as widespread organelles, are involved in regulation of complex biological processes such as energy synthesis and cell metabolism, which also have bidirectional communication with the nucleus to help maintain cellular homeostasis and regulate adaptation to a broad range of stressors. In light of the evidence that OA is strongly associated with mitochondrial dysfunction. In addition, mitochondria are considered to be the culprits of cell senescence, and mitochondrial function changes during ageing are considered to have a controlling role in cell fate. Mitochondrial dysfunction is also observed in age-related OA, however, the internal mechanism by which mitochondrial function changes with ageing to lead to the development of OA has not been elucidated. In this study, we found that the expression of Lon protease 1 (LONP1), a mitochondrial protease, was decreased in human OA cartilage and in ageing rat chondrocytes. Furthermore, LONP1 knockdown accelerated the progression and severity of osteoarthritis, which was associated with aspects of mitochondrial dysfunction including oxidative stress, metabolic changes and mitophagy, leading to downstream MAPK pathway activation. Antioxidant therapy with resveratrol suppressed oxidative stress and MAPK pathway activation induced by LONP1 knockdown to mitigate OA progression. Therefore, our findings demonstrate that LONP1 is a central regulator of mitochondrial function in chondrocytes and reveal that downregulation of LONP1 with ageing contributes to osteoarthritis.
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Affiliation(s)
- Yuzhe He
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China
| | - Qianhai Ding
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China
| | - Wenliang Chen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China
| | - Changjian Lin
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China
| | - Lujie Ge
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China
| | - Chenting Ying
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China
| | - Kai Xu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China
| | - Zhipeng Wu
- Department of Orthopaedics, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
| | - Langhai Xu
- Department of Pain, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Jisheng Ran
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China
| | - Weiping Chen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China.
| | - Lidong Wu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China.
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22
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He S, Shi J, Liu W, Du S, Zhang Y, Gong L, Dong S, Li X, Gao Q, Yang J, Yu J. Heme oxygenase-1 protects against endotoxin-induced acute lung injury depends on NAD +-mediated mitonuclear communication through PGC1α/PPARγ signaling pathway. Inflamm Res 2022; 71:1095-1108. [PMID: 35816227 PMCID: PMC9272656 DOI: 10.1007/s00011-022-01605-y] [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: 04/26/2022] [Accepted: 06/28/2022] [Indexed: 12/27/2022] Open
Abstract
Endotoxin-induced acute lung injury (ALI) is a challenging life-threatening disease for which no specific therapy exists. Mitochondrial dysfunction is corroborated as hallmarks in sepsis which commonly disrupt mitochondria-centered cellular communication networks, especially mitonuclear crosstalk, where the ubiquitous cofactor nicotinamide adenine dinucleotide (NAD+) is essential for mitonuclear communication. Heme oxygenase-1 (HO-1) is critical for maintaining mitochondrial dynamic equilibrium and regulating endoplasmic reticulum (ER) and Golgi stress to alleviating acute lung injury. However, it is unclear whether HO-1 regulates NAD+-mediated mitonuclear communication to exert the endogenous protection during endotoxin-induced ALI. In this study, we observed HO-1 attenuated endotoxin-induced ALI by regulated NAD+ levels and NAD+ affected the mitonuclear communication, including mitonuclear protein imbalance and UPRmt to alleviate lung damage. We also found the protective effect of HO-1 depended on NAD+ and NAD+-mediated mitonuclear communication. Furtherly, the inhibition of the PGC1α/PPARγ signaling exacerbates the septic lung injury by reducing NAD+ levels and repressing the mitonuclear protein imbalance and UPRmt. Altogether, our study certified that HO-1 ameliorated endotoxin-induced acute lung injury by regulating NAD+ and NAD+-mediated mitonuclear communications through PGC1α/PPARγ pathway. The present study provided complementary evidence for the cytoprotective effect of HO-1 as a potential target for preventing and attenuating of endotoxin-induced ALI.
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Affiliation(s)
- Simeng He
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
| | - Jia Shi
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
| | - Wenming Liu
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
| | - Shihan Du
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
| | - Yuan Zhang
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
| | - Lirong Gong
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
| | - Shuan Dong
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
| | - Xiangyun Li
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
| | - Qiaoying Gao
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Tianjin, China
| | - Jing Yang
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Tianjin, China
| | - Jianbo Yu
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China.
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23
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Du SH, Shi J, Yu TY, Hu XX, He SM, Cao YY, Xie ZL, Liu SS, Li YT, Li N, Yu JB. Nicotinamide mononucleotide ameliorates acute lung injury by inducing mitonuclear protein imbalance and activating the UPR mt. Exp Biol Med (Maywood) 2022; 247:1264-1276. [PMID: 35538652 PMCID: PMC9379602 DOI: 10.1177/15353702221094235] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Mitochondria need to interact with the nucleus under homeostasis and stress to maintain cellular demands and nuclear transcriptional programs. Disrupted mitonuclear interaction is involved in many disease processes. However, the role of mitonuclear signaling regulators in endotoxin-induced acute lung injury (ALI) remains unknown. Nicotinamide adenine dinucleotide (NAD+) is closely related to mitonuclear interaction with its central role in mitochondrial metabolism. In the current study, C57BL/6J mice were administrated with lipopolysaccharide 15 mg/kg to induce endotoxin-induced ALI and investigated whether the NAD+ precursor nicotinamide mononucleotide (NMN) could preserve mitonuclear interaction and alleviate ALI. After pretreatment with NMN for 7 days, NAD+ levels in the mitochondrial, nucleus, and total intracellular were significantly increased in endotoxemia mice. Moreover, supplementation of NMN alleviated lung pathologic injury, reduced ROS levels, increased MnSOD activities, mitigated mitochondrial dysfunction, ameliorated the defects in the nucleus morphology, and these cytoprotective effects were accompanied by preserving mitonuclear interaction (including mitonuclear protein imbalance and the mitochondrial unfolded protein response, UPRmt). Furthermore, NAD+-mediated mitonuclear protein imbalance and UPRmt are probably regulated by deacetylase Sirtuin1 (SIRT1). Taken together, our results indicated that NMN pretreatment ameliorated ALI by inducing mitonuclear protein imbalance and activating the UPRmt in an SIRT1-dependent manner.
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Affiliation(s)
- Shi-Han Du
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China
| | - Jia Shi
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China
| | - Tian-Yu Yu
- Tianjin Medical University, Tianjin 300070, China
| | - Xin-Xin Hu
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China
| | - Si-Meng He
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, NanKai University, Tianjin 300071, China
| | - Ying-Ya Cao
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China
| | - Zi-Lei Xie
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China
| | - Sha-Sha Liu
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China
| | - Yu-Ting Li
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China
| | - Na Li
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China
| | - Jian-Bo Yu
- Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China,Jian-Bo Yu.
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24
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Li J, Wang Z, Li C, Song Y, Wang Y, Bo H, Zhang Y. Impact of Exercise and Aging on Mitochondrial Homeostasis in Skeletal Muscle: Roles of ROS and Epigenetics. Cells 2022; 11:cells11132086. [PMID: 35805170 PMCID: PMC9266156 DOI: 10.3390/cells11132086] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/22/2022] [Accepted: 06/28/2022] [Indexed: 02/01/2023] Open
Abstract
Aging causes degenerative changes such as epigenetic changes and mitochondrial dysfunction in skeletal muscle. Exercise can upregulate muscle mitochondrial homeostasis and enhance antioxidant capacity and represents an effective treatment to prevent muscle aging. Epigenetic changes such as DNA methylation, histone posttranslational modifications, and microRNA expression are involved in the regulation of exercise-induced adaptive changes in muscle mitochondria. Reactive oxygen species (ROS) play an important role in signaling molecules in exercise-induced muscle mitochondrial health benefits, and strong evidence emphasizes that exercise-induced ROS can regulate gene expression via epigenetic mechanisms. The majority of mitochondrial proteins are imported into mitochondria from the cytosol, so mitochondrial homeostasis is regulated by nuclear epigenetic mechanisms. Exercise can reverse aging-induced changes in myokine expression by modulating epigenetic mechanisms. In this review, we provide an overview of the role of exercise-generated ROS in the regulation of mitochondrial homeostasis mediated by epigenetic mechanisms. In addition, the potential epigenetic mechanisms involved in exercise-induced myokine expression are reviewed.
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Affiliation(s)
- Jialin Li
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China; (J.L.); (Z.W.); (C.L.); (Y.S.); (Y.W.)
| | - Zhe Wang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China; (J.L.); (Z.W.); (C.L.); (Y.S.); (Y.W.)
| | - Can Li
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China; (J.L.); (Z.W.); (C.L.); (Y.S.); (Y.W.)
| | - Yu Song
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China; (J.L.); (Z.W.); (C.L.); (Y.S.); (Y.W.)
| | - Yan Wang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China; (J.L.); (Z.W.); (C.L.); (Y.S.); (Y.W.)
| | - Hai Bo
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China; (J.L.); (Z.W.); (C.L.); (Y.S.); (Y.W.)
- Department of Military Training Medicines, Logistics University of Chinese People’s Armed Police Force, Tianjin 300162, China
- Correspondence: (H.B.); (Y.Z.)
| | - Yong Zhang
- Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Institute of Exercise and Health, Tianjin University of Sport, Tianjin 301617, China; (J.L.); (Z.W.); (C.L.); (Y.S.); (Y.W.)
- Correspondence: (H.B.); (Y.Z.)
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25
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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.
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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
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26
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Rovina RL, Pinto AP, Muñoz VR, da Rocha AL, Rebelo MA, Teixeira GR, Tavares MEA, Pauli JR, de Moura LP, Cintra DE, Ropelle ER, da Silva ASR. Genetic deletion of IL-6 increases CK-MB, a classic cardiac damage marker, and decreases UPRmt genes after exhaustive exercise. Cell Biochem Funct 2022; 40:369-378. [PMID: 35411956 DOI: 10.1002/cbf.3701] [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] [Received: 03/11/2022] [Revised: 03/25/2022] [Accepted: 03/30/2022] [Indexed: 11/10/2022]
Abstract
The intensity, duration, type of contraction, and muscle damage influence interleukin-6 (IL-6) response to acute exercise. However, in response to an exhaustive exercise session, the upregulation of IL-6 in the serum and heart is associated with an inflammatory condition and can inhibit autophagy. This study aimed to investigate the role of IL-6 in autophagy pathway responses and mitochondrial function in the heart of mice submitted to acute exhaustive physical exercise. The mice were allocated into three groups, five animals per group, for the wild type (WT) and the IL-6 knockout (IL-6 KO): Basal (sedentary; Basal), 1 h (after 1 h of the acute exercise; 1 h), and 3 h (after 3 h of the acute exercise; 3 h). After the specific time for each group, the blood was collected, each mouse heart was removed, and the left ventricle (LV) was isolated. In summary, under basal conditions, without the influence of the acute exercise, the IL-6 KO group showed lower number of nuclei in the cardiac tissue, but higher collagen deposition; lower messenger RNA (mRNA) levels of Prkaa1 and Mtco1, but higher mRNA levels of Ulk1; and higher protein levels of the ratio p-AMPK/AMPK in the heart when compared to WT at the same time point. After the acute exercise (1 and 3 h), the IL-6 KO group had lower mRNA levels of Tfam, Mtnd1, Mtco1, and Nampt in the heart when compared to WT after exercise; higher serum levels of creatine kinase (CK), CK-MB, and lactate dehydrogenase for the IL-6 group when compared to the WT group after the exercise. Specifically, the heat-shock protein 60 protein levels in the heart increased 3 h after exhaustive exercise in the WT group, but not in the IL-6 KO group. The study emphasizes that IL-6 may offer cardioprotective effects, including mitochondrial adaptations in response to acute exhaustive exercise.
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Affiliation(s)
- Rafael L Rovina
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Ana P Pinto
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Vitor R Muñoz
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Alisson L da Rocha
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Macario A Rebelo
- Department of Pharmacology, Faculty of Medicinal Sciences, State University of Campinas (UNICAMP), University of Campinas, Campinas, São Paulo, Brazil
| | - Giovana R Teixeira
- Multicentric Program of Postgraduate in Physiological Sciences, School of Dentistry of Araçatuba, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil.,Department of Physical Education, State University of São Paulo (UNESP), Presidente Prudente, São Paulo, Brazil
| | - Maria Eduarda A Tavares
- Multicentric Program of Postgraduate in Physiological Sciences, School of Dentistry of Araçatuba, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil
| | - José R Pauli
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Leandro P de Moura
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Dennys E Cintra
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Eduardo R Ropelle
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Adelino S R da Silva
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.,Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
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27
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Slavin MB, Memme JM, Oliveira AN, Moradi N, Hood DA. Regulatory networks controlling mitochondrial quality control in skeletal muscle. Am J Physiol Cell Physiol 2022; 322:C913-C926. [PMID: 35353634 DOI: 10.1152/ajpcell.00065.2022] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The adaptive plasticity of mitochondria within skeletal muscle is regulated by signals converging on a myriad of regulatory networks that operate during conditions of increased (i.e. exercise) and decreased (inactivity, disuse) energy requirements. Notably, some of the initial signals that induce adaptive responses are common to both conditions, differing in their magnitude and temporal pattern, to produce vastly opposing mitochondrial phenotypes. In response to exercise, signaling to PGC-1α and other regulators ultimately produces an abundance of high quality mitochondria, leading to reduced mitophagy and a higher mitochondrial content. This is accompanied by the presence of an enhanced protein quality control system that consists of the protein import machinery as well chaperones and proteases termed the UPRmt. The UPRmt monitors intra-organelle proteostasis, and strives to maintain a mito-nuclear balance between nuclear- and mtDNA-derived gene products via retrograde signaling from the organelle to the nucleus. In addition, antioxidant capacity is improved, affording greater protection against oxidative stress. In contrast, chronic disuse conditions produce similar signaling but result in decrements in mitochondrial quality and content. Thus, the interactive cross-talk of the regulatory networks that control organelle turnover during wide variations in muscle use and disuse remain incompletely understood, despite our improving knowledge of the traditional regulators of organelle content and function. This brief review acknowledges existing regulatory networks and summarizes recent discoveries of novel biological pathways involved in determining organelle biogenesis, dynamics, mitophagy, protein quality control and antioxidant capacity, identifying ample protein targets for therapeutic intervention that determine muscle and mitochondrial health.
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Affiliation(s)
- Mikhaela B Slavin
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.,School of Kinesiology and Health Science, York University, Toronto, ON, Canada
| | - Jonathan M Memme
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.,School of Kinesiology and Health Science, York University, Toronto, ON, Canada
| | - Ashley N Oliveira
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.,School of Kinesiology and Health Science, York University, Toronto, ON, Canada
| | - Neushaw Moradi
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.,School of Kinesiology and Health Science, York University, Toronto, ON, Canada
| | - David A Hood
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.,School of Kinesiology and Health Science, York University, Toronto, ON, Canada
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From the Bench to the Bedside: Branched Amino Acid and Micronutrient Strategies to Improve Mitochondrial Dysfunction Leading to Sarcopenia. Nutrients 2022; 14:nu14030483. [PMID: 35276842 PMCID: PMC8838610 DOI: 10.3390/nu14030483] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/17/2022] [Accepted: 01/19/2022] [Indexed: 02/01/2023] Open
Abstract
With extended life expectancy, the older population is constantly increasing, and consequently, so too is the prevalence of age-related disorders. Sarcopenia, the pathological age-related loss of muscle mass and function; and malnutrition, the imbalance in nutrient intake and resultant energy production, are both commonly occurring conditions in old adults. Altered nutrition plays a crucial role in the onset of sarcopenia, and both these disorders are associated with detrimental consequences for patients (e.g., frailty, morbidity, and mortality) and society (e.g., healthcare costs). Importantly, sarcopenia and malnutrition also share critical molecular alterations, such as mitochondrial dysfunction, increased oxidative stress, and a chronic state of low grade and sterile inflammation, defined as inflammageing. Given the connection between malnutrition and sarcopenia, nutritional interventions capable of affecting mitochondrial health and correcting inflammageing are emerging as possible strategies to target sarcopenia. Here, we discuss mitochondrial dysfunction, oxidative stress, and inflammageing as key features leading to sarcopenia. Moreover, we examine the effects of some branched amino acids, omega-3 PUFA, and selected micronutrients on these pathways, and their potential role in modulating sarcopenia, warranting further clinical investigation.
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29
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Ehrlich KC, Deng HW, Ehrlich M. Epigenetics of Mitochondria-Associated Genes in Striated Muscle. EPIGENOMES 2021; 6:1. [PMID: 35076500 PMCID: PMC8788487 DOI: 10.3390/epigenomes6010001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 12/04/2021] [Accepted: 12/16/2021] [Indexed: 11/16/2022] Open
Abstract
Striated muscle has especially large energy demands. We identified 97 genes preferentially expressed in skeletal muscle and heart, but not in aorta, and found significant enrichment for mitochondrial associations among them. We compared the epigenomic and transcriptomic profiles of the 27 genes associated with striated muscle and mitochondria. Many showed strong correlations between their tissue-specific transcription levels, and their tissue-specific promoter, enhancer, or open chromatin as well as their DNA hypomethylation. Their striated muscle-specific enhancer chromatin was inside, upstream, or downstream of the gene, throughout much of the gene as a super-enhancer (CKMT2, SLC25A4, and ACO2), or even overlapping a neighboring gene (COX6A2, COX7A1, and COQ10A). Surprisingly, the 3' end of the 1.38 Mb PRKN (PARK2) gene (involved in mitophagy and linked to juvenile Parkinson's disease) displayed skeletal muscle/myoblast-specific enhancer chromatin, a myoblast-specific antisense RNA, as well as brain-specific enhancer chromatin. We also found novel tissue-specific RNAs in brain and embryonic stem cells within PPARGC1A (PGC-1α), which encodes a master transcriptional coregulator for mitochondrial formation and metabolism. The tissue specificity of this gene's four alternative promoters, including a muscle-associated promoter, correlated with nearby enhancer chromatin and open chromatin. Our in-depth epigenetic examination of these genes revealed previously undescribed tissue-specific enhancer chromatin, intragenic promoters, regions of DNA hypomethylation, and intragenic noncoding RNAs that give new insights into transcription control for this medically important set of genes.
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Affiliation(s)
- Kenneth C. Ehrlich
- Center for Bioinformatics and Genomics, Tulane University Health Sciences Center, New Orleans, LA 70112, USA; (K.C.E.); (H.-W.D.)
| | - Hong-Wen Deng
- Center for Bioinformatics and Genomics, Tulane University Health Sciences Center, New Orleans, LA 70112, USA; (K.C.E.); (H.-W.D.)
| | - Melanie Ehrlich
- Center for Bioinformatics and Genomics, Tulane University Health Sciences Center, New Orleans, LA 70112, USA; (K.C.E.); (H.-W.D.)
- Tulane Cancer Center and Hayward Genetics Center, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
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30
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Mitochondrial dysfunction plays an essential role in remodeling aging adipose tissue. Mech Ageing Dev 2021; 200:111598. [PMID: 34762939 DOI: 10.1016/j.mad.2021.111598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/12/2021] [Accepted: 11/03/2021] [Indexed: 11/22/2022]
Abstract
Aging is characterized by several physiological changes in the human body, such as the remodeling/redistribution of body fat, highlighted by the increase in fat in the abdominal region due to reduced fat in the peripheral limbs. Abdominal fat is related to metabolic complications and an increased risk for developing diseases such as obesity, type 2 diabetes mellitus, and hypertension. Understanding this process is crucial for developing new therapeutic strategies able to mitigate its impact. This redistribution of fat has been associated with lower activation of brown adipose tissue over the years of life. Brown adipose tissue differs from white adipose tissue, mainly because it produces heat, increasing energy expenditure. Current evidence points to morphological and functional changes in mitochondria during aging, a key mechanism for understanding the dysmetabolic and pro-inflammatory phenotype associated with senescence. Therefore, this minireview will focus on how aging-induced mitochondrial changes are involved in the remodeling/redistribution of body fat.
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31
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Gu LF, Chen JQ, Lin QY, Yang YZ. Roles of mitochondrial unfolded protein response in mammalian stem cells. World J Stem Cells 2021; 13:737-752. [PMID: 34367475 PMCID: PMC8316864 DOI: 10.4252/wjsc.v13.i7.737] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 05/13/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved adaptive mechanism for improving cell survival under mitochondrial stress. Under physiological and pathological conditions, the UPRmt is the key to maintaining intracellular homeostasis and proteostasis. Important roles of the UPRmt have been demonstrated in a variety of cell types and in cell development, metabolism, and immune processes. UPRmt dysfunction leads to a variety of pathologies, including cancer, inflammation, neurodegenerative disease, metabolic disease, and immune disease. Stem cells have a special ability to self-renew and differentiate into a variety of somatic cells and have been shown to exist in a variety of tissues. These cells are involved in development, tissue renewal, and some disease processes. Although the roles and regulatory mechanisms of the UPRmt in somatic cells have been widely reported, the roles of the UPRmt in stem cells are not fully understood. The roles and functions of the UPRmt depend on stem cell type. Therefore, this paper summarizes the potential significance of the UPRmt in embryonic stem cells, tissue stem cells, tumor stem cells, and induced pluripotent stem cells. The purpose of this review is to provide new insights into stem cell differentiation and tumor pathogenesis.
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Affiliation(s)
- Li-Fang Gu
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Jia-Qi Chen
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Qing-Yin Lin
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yan-Zhou Yang
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750001, Ningxia Hui Autonomous Region, China.
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32
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Gibbs KW, Chuang Key CC, Belfield L, Krall J, Purcell L, Liu C, Files DC. Aging Influences the Metabolic and Inflammatory Phenotype in an Experimental Mouse Model of Acute Lung Injury. J Gerontol A Biol Sci Med Sci 2021; 76:770-777. [PMID: 32997738 PMCID: PMC8087268 DOI: 10.1093/gerona/glaa248] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Indexed: 01/16/2023] Open
Abstract
Increased age is a risk factor for poor outcomes from respiratory failure and acute respiratory distress syndrome (ARDS). In this study, we sought to define age-related differences in lung inflammation, muscle injury, and metabolism after intratracheal lipopolysaccharide (IT-LPS) acute lung injury (ALI) in adult (6 months) and aged (18-20 months) male C57BL/6 mice. We also investigated age-related changes in muscle fatty acid oxidation (FAO) and the consequences of systemic FAO inhibition with the drug etomoxir. Aged mice had a distinct lung injury course characterized by prolonged alveolar neutrophilia and lack of response to therapeutic exercise. To assess the metabolic consequences of ALI, aged and adult mice underwent whole body metabolic phenotyping before and after IT-LPS. Aged mice had prolonged anorexia and decreased respiratory exchange ratio, indicating increased reliance on FAO. Etomoxir increased mortality in aged but not adult ALI mice, confirming the importance of FAO on survival from acute severe stress and suggesting that adult mice have increased resilience to FAO inhibition. Skeletal muscles from aged ALI mice had increased transcription of key fatty acid metabolizing enzymes, CPT-1b, LCAD, MCAD, FATP1 and UCP3. Additionally, aged mice had increased protein levels of CPT-1b at baseline and after lung injury. Surprisingly, CPT-1b in isolated skeletal muscle mitochondria had decreased activity in aged mice compared to adults. The distinct phenotype of aged ALI mice has similar characteristics to the adverse age-related outcomes of ARDS. This model may be useful to examine and augment immunologic and metabolic abnormalities unique to the critically ill aged population.
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Affiliation(s)
- Kevin W Gibbs
- Department of Internal Medicine, Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, North Carolina
- Wake Forest Critical Illness, Injury, and Recovery Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Chia-Chi Chuang Key
- Department of Internal Medicine, Molecular Medicine, Wake Forest School of Medicine Winston-Salem, North Carolina
| | - Lanazha Belfield
- Department of Internal Medicine, Molecular Medicine, Wake Forest School of Medicine Winston-Salem, North Carolina
| | - Jennifer Krall
- Department of Internal Medicine, Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Lina Purcell
- Department of Internal Medicine, Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Chun Liu
- Department of Internal Medicine, Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - D Clark Files
- Department of Internal Medicine, Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, North Carolina
- Wake Forest Critical Illness, Injury, and Recovery Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina
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33
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Zhu L, Zhou Q, He L, Chen L. Mitochondrial unfolded protein response: An emerging pathway in human diseases. Free Radic Biol Med 2021; 163:125-134. [PMID: 33347985 DOI: 10.1016/j.freeradbiomed.2020.12.013] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 11/20/2020] [Accepted: 12/10/2020] [Indexed: 12/14/2022]
Abstract
Mitochondrial unfolded protein response (UPRmt) is a mitochondria stress response, which the transcriptional activation programs of mitochondrial chaperone proteins and proteases are initiated to maintain proteostasis in mitochondria. Additionally, the activation of UPRmt delays aging and extends lifespan by maintaining mitochondrial proteostasis. Growing evidences suggests that UPRmt plays an important role in diverse human diseases, especially ageing-related diseases. Therefore, this review focuses on the role of UPRmt in ageing and ageing-related neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease. The activation of UPRmt and the high expression of UPRmt components contribute to longevity extension. The activation of UPRmt may ameliorate Alzheimer's disease, Parkinson's disease and Huntington's disease. Besides, UPRmt is also involved in the occurrence and development of cancers and heart diseases. UPRmt contributes to the growth, invasive and metastasis of cancers. UPRmt has paradoxical roles in heart diseases. UPRmt not only protects against heart damage, but may sometimes aggravates the development of heart diseases. Considering the pleiotropic actions of UPRmt system, targeting UPRmt pathway may be a potent therapeutic avenue for neurodegenerative diseases, cancers and heart diseases.
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Affiliation(s)
- Li Zhu
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, Hunan, China
| | - Qionglin Zhou
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, Hunan, China
| | - Lu He
- Department of Pharmacy, The First Affiliated Hospital, University of South China, Hengyang, China.
| | - Linxi Chen
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, Hunan, China.
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34
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Urbina-Varela R, Castillo N, Videla LA, del Campo A. Impact of Mitophagy and Mitochondrial Unfolded Protein Response as New Adaptive Mechanisms Underlying Old Pathologies: Sarcopenia and Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2020; 21:E7704. [PMID: 33081022 PMCID: PMC7589512 DOI: 10.3390/ijms21207704] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/08/2020] [Accepted: 10/12/2020] [Indexed: 12/12/2022] Open
Abstract
Mitochondria are the first-line defense of the cell in the presence of stressing processes that can induce mitochondrial dysfunction. Under these conditions, the activation of two axes is accomplished, namely, (i) the mitochondrial unfolded protein response (UPRmt) to promote cell recovery and survival of the mitochondrial network; (ii) the mitophagy process to eliminate altered or dysfunctional mitochondria. For these purposes, the former response induces the expression of chaperones, proteases, antioxidant components and protein import and assembly factors, whereas the latter is signaled through the activation of the PINK1/Parkin and BNIP3/NIX pathways. These adaptive mechanisms may be compromised during aging, leading to the development of several pathologies including sarcopenia, defined as the loss of skeletal muscle mass and performance; and non-alcoholic fatty liver disease (NAFLD). These age-associated diseases are characterized by the progressive loss of organ function due to the accumulation of reactive oxygen species (ROS)-induced damage to biomolecules, since the ability to counteract the continuous and large generation of ROS becomes increasingly inefficient with aging, resulting in mitochondrial dysfunction as a central pathogenic mechanism. Nevertheless, the role of the integrated stress response (ISR) involving UPRmt and mitophagy in the development and progression of these illnesses is still a matter of debate, considering that some studies indicate that the prolonged exposure to low levels of stress may trigger these mechanisms to maintain mitohormesis, whereas others sustain that chronic activation of them could lead to cell death. In this review, we discuss the available research that contributes to unveil the role of the mitochondrial UPR in the development of sarcopenia, in an attempt to describe changes prior to the manifestation of severe symptoms; and in NAFLD, in order to prevent or reverse fat accumulation and its progression by means of suitable protocols to be addressed in future studies.
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Affiliation(s)
- Rodrigo Urbina-Varela
- Laboratorio de Fisiología y Bioenergética Celular, Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 7810000, Chile; (R.U.-V.); (N.C.)
| | - Nataly Castillo
- Laboratorio de Fisiología y Bioenergética Celular, Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 7810000, Chile; (R.U.-V.); (N.C.)
| | - Luis A. Videla
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 8380453, Chile;
| | - Andrea del Campo
- Laboratorio de Fisiología y Bioenergética Celular, Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 7810000, Chile; (R.U.-V.); (N.C.)
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35
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High-intensity exercise training induces mitonuclear imbalance and activates the mitochondrial unfolded protein response in the skeletal muscle of aged mice. GeroScience 2020; 43:1513-1518. [PMID: 32737758 DOI: 10.1007/s11357-020-00246-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 07/29/2020] [Indexed: 12/15/2022] Open
Abstract
The impairment of mitochondrial metabolism is a hallmark of aging. Mitonuclear imbalance and the mitochondrial unfolded protein response (UPRmt) are two conserved mitochondrial mechanisms that play critical roles in ensuring mitochondrial proteostasis and function. Here, we combined bioinformatics, physiological, and molecular analyses to examine the role of mitonuclear imbalance and UPRmt in the skeletal muscle of aged rodents and humans. The analysis of transcripts from the skeletal muscle of aged humans (60-70 years old) revealed that individuals with higher levels of UPRmt-related genes displayed a consistent increase in several mitochondrial-related genes, including the OXPHOS-associated genes. Interestingly, high-intensity interval training (HIIT) was effective in stimulating the mitonuclear imbalance and UPRmt in the skeletal muscle of aged mice. Furthermore, these results were accompanied by higher levels of several mitochondrial markers and improvements in physiological parameters and physical performance. These data indicate that the maintenance or stimulation of the mitonuclear imbalance and UPRmt in the skeletal muscle could ensure mitochondrial proteostasis during aging, revealing new insights into targeting mitochondrial metabolism by using physical exercise.
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