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Enhanced Respiratory Chain Supercomplex Formation in Response to Exercise in Human Skeletal Muscle
Open accessAbstract
Mitochondrial dysfunction is a hallmark of multiple metabolic complications. Physical activity is known to increase mitochondrial content in skeletal muscle, counteracting age-related decline in muscle function and protecting against metabolic and cardiovascular complications. Here, we investigated the effect of 4 months of exercise training on skeletal muscle mitochondria electron transport chain complexes and supercomplexes in 26 healthy, sedentary older adults. Exercise differentially modulated respiratory complexes. Complex I was the most upregulated complex and not stoichiometrically associated to the other complexes. In contrast to the other complexes, complex I was almost exclusively found assembled in supercomplexes in muscle mitochondria. Overall, supercomplex content was increased after exercise. In particular, complexes I, III, and IV were redistributed to supercomplexes in the form of I+III 2+IV. Taken together, our results provide the first evidence that exercise affects the stoichiometry of supercomplex formation in humans and thus reveal a novel adaptive mechanism for increased energy demand.
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“Endurance exercise increases the activity of muscle oxidative enzymes and FAO, in part from increased volume of the mitochondrial reticulum and elevated levels of cardiolipin, a lipid that is necessary for the assembly of OXPHOS complexes (41, 51, 225).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [225]
In the citing paper
“The established benefits of physical activity on mitochondrial efficiency in aged skeletal muscle2,47,59”
From Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities (2019) · cites this paper as [47]
In the citing paper
“Instead, mitochondria electron transport chain supercomplex assembly is promoted by exercise (Figure 3) and resulted in increased maximal O2 consumption and mitochondrial respiratory capacity as well as increased reliance on fatty acid oxidation during exercise (Greggio et al., 2017).”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Greggio et al., 2017
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BackgroundMass-spectrometry-based proteomics reveals mitochondrial supercomplexome plasticity
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“Proteins in CI, CII, and CV all primarily correlated with proteins within the same complex, whereas proteins in CIII and CIV had equally strong and prevalent correlations across complex as within, mirroring the observations that CIII and CIV proteins are especially prone to dynamic interactions with other complexes (4…”
BackgroundSelf-citationPeroxisomal-derived ether phospholipids link nucleotides to respirasome assembly
Bennett, C. F., O’Malley, K. E., Perry, E. A., Balsa, E., Latorre‐Muro, P., Riley, C. L., Luo, C., Jedrychowski, M. P., Gygi, S. P., & Puigserver, P. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00772-z · Cited by 49
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Acute RyR1 Ca2+ leak enhances NADH-linked mitochondrial respiratory capacity
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Self-citationExercise-Regulated Mitochondrial and Nuclear Signalling Networks in Skeletal Muscle
Reisman, E. G., Hawley, J. A., & Hoffman, N. J. (2024) · Sports Medicine · doi:10.1007/s40279-024-02007-2 · Cited by 57
“Mitochondrial biogenesis is therefore typically recognised as the production of these new mitochondrial components [40, 41], the outcomes of which include alterations in mitochondrial quality (i.e. cristae density), respiratory function and/or content [42–44].”
BackgroundIntracellular to Interorgan Mitochondrial Communication in Striated Muscle in Health and Disease
Boardman, N. T., Trani, G., Scalabrin, M., Romanello, V., & Wüst, R. C. I. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnad004 · Cited by 51
Molecular and biochemical regulation of skeletal muscle metabolism
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Regulation of myogenic cell proliferation and differentiation during mammalian skeletal myogenesis
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Self-citationSheng, Y., Hu, W., Chen, S., & Zhu, X. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1275203 · Cited by 50
“An increasing number of clinical trials have investigated non-nucleotide metabolic drugs targeting the electron transport chain (175, 176), asparagine synthetase (176), 3-hydroxy-3-methylglutaryl-CoA reductase (177), indoleamine 2,3-dioxygenase-1 (178), and mutated isocitrate dehydrogenase (IDH)-1.”
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“Alterations in SCs have been described in brain and muscle during aging, and interestingly, besides increasing individual MRC subunits, exercise affects the stoichiometry of SC formation in old age (Greggio et al., 2017).”
BackgroundApproaches to monitor ATP levels in living cells: where do we stand?
Ley‐Ngardigal, S., & Bertolin, G. (2021) · FEBS Journal · doi:10.1111/febs.16169 · Cited by 51
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Functional segmentation of CoQ and cyt c pools by respiratory complex superassembly
Hernansanz‐Agustín, P., & Enrı́quez, J. A. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.03.010 · Cited by 37
Single-cell RNA sequencing in skeletal muscle developmental biology
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Passing the Baton: Substrate Channelling in Respiratory Metabolism
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NDUFAB1 protects against obesity and insulin resistance by enhancing mitochondrial metabolism
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“Exercise intervention was shown to induce respiratory chain supercomplex formation [86].”
BackgroundCOX17 acetylation via MOF–KANSL complex promotes mitochondrial integrity and function
Guhathakurta, S., Erdogdu, N. U., Hoffmann, J. J., Grządzielewska, I., Schendzielorz, A. B., Seyfferth, J., Mårtensson, C. U., Corrado, M., Karoutas, A., Warscheid, B., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00904-w · Cited by 39
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Targeting mitochondrial function and proteostasis to mitigate dynapenia
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“First, the maintenance of mitochondrial proteins facilitates the coupling of electron transport system to ATP production (Zangarelli et al. 2006; Greggio et al. 2017), thus decreasing ROS production.”
BackgroundCerqueira, F. M., von Stockum, S., Giacomello, M., Goliand, I., Kakimoto, P. A., Marchesan, E., Stefani, D. D., Kowaltowski, A. J., Ziviani, E., & Shirihai, O. S. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101676 · Cited by 40
“In isolated mitochondria, maximum OCR may reflect differences in super-complex content, activity and assembly, NAD availability, membrane composition, levels and activity of proteins of the respiratory chain, and many other effects [51,67,68].”
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Human muscular mitochondrial fusion in athletes during exercise
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“The morphologic changes in response to alteredenergeticdemandsappear tobeofdecisive importance for supporting the required cellular energy demand (3, 10).”
BackgroundResearch journey of respirasome
Wu, M., Gu, J., Zong, S., Guo, R., Liu, T., & Yang, M. (2020) · Protein & Cell · doi:10.1007/s13238-019-00681-x · Cited by 35
“Many evidence show that the individual complexes could assemble into supercomplexes (I1III2IV1–2, III2IV1–2), or even megacomplex (I2III2IV2) (Schägger and Pfeiffer, 2000; Schagger and Pfeiffer, 2001; Bultema et al., 2009; Mileykovskaya et al., 2012; Greggio et al., 2017; Guo et al., 2017).”
BackgroundExercise training enhances muscle mitochondrial metabolism in diet-resistant obesity
Pileggi, C. A., Blondin, D. P., Hooks, B. G., Parmar, G., Alecu, I., Patten, D. A., Cuillerier, A., O’Dwyer, C., Thrush, A. B., Fullerton, M. D., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.104192 · Cited by 37
Novel insights into the mechanism of electron transfer in mitochondrial cytochrome c
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Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
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COX7A2L genetic variants determine cardiorespiratory fitness in mice and human
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Self-citationMitochondria in Embryogenesis: An Organellogenesis Perspective
Arribat, Y., Grepper, D., Lagarrigue, S., Richard, J., Gachet, M., Gut, P., & Amati, F. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00282 · Cited by 35
Self-citation
Metadata
- Authors
- Greggio, C., Jha, P., Kulkarni, S. S., Lagarrigue, S., Broskey, N. T., Boutant, M., Wang, X., Conde Alonso, S., Ofori, E., Auwerx, J., Cantó, C., & Amati, F.
- Affiliations
- University of Lausanne (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- Centre Hospitalier Universitaire Vaudois (CH)
- Corresponding author
- Auwerx, Johan
- Cantó, Carles
- Amati, Francesca
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 25
- Issue
- 2
- Pages
- 301-311
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2558143992
- Cited by
- 286
- References
- 52
- Citations by year
- 2026: 21 · 2025: 31 · 2024: 34 · 2023: 26 · 2022: 28 · 2021: 42 · 2020: 36 · 2019: 27 · 2018: 29 · 2017: 12
- FWCI
- 11.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 371 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- IRIS (submittedVersion, cc-by-nc)
- SERVAL (Université de Lausanne) (submittedVersion, cc-by-nc)
- Funders
- Swiss National Science Foundation (SNSF) (PZ00P3-126339, PZ00P3-149398, 320030_170062)
- Leenaards Foundation
- BASPO
- EPFL
- NIH (R01AG043930)
- Systems X (SySX.ch 2013/153)
- SNSF (31003A-140780)
- EU Marie Skłodowska-Curie ITN (H2020-MSCA-ITN-2015-ChroMe - 675610)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
- Keywords
- respiratory chain supercomplexes, exercise training, skeletal muscle mitochondria, respiratory chain complexes, complex I, cytochrome bc1 complex, cytochrome c oxidase, mitochondrial biogenesis, mitochondrial dysfunction, older adults, energy demand
- MeSH terms
- Aged, Aging, Female, Humans, Male, Middle Aged, Oxygen, Exercise, Muscle, Skeletal, Cell Respiration, Electron Transport Chain Complex Proteins, Adiposity
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