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Sites of Superoxide and Hydrogen Peroxide Production by Muscle Mitochondria Assessed ex Vivo under Conditions Mimicking Rest and Exercise
Open accessAbstract
The sites and rates of mitochondrial production of superoxide and H 2 O 2 in vivo are not yet defined. At least 10 different mitochondrial sites can generate these species. Each site has a different maximum capacity ( e.g. the outer quinol site in complex III (site III Qo ) has a very high capacity in rat skeletal muscle mitochondria, whereas the flavin site in complex I (site I F ) has a very low capacity). The maximum capacities can greatly exceed the actual rates observed in the absence of electron transport chain inhibitors, so maximum capacities are a poor guide to actual rates. Here, we use new approaches to measure the rates at which different mitochondrial sites produce superoxide/H 2 O 2 using isolated muscle mitochondria incubated in media mimicking the cytoplasmic substrate and effector mix of skeletal muscle during rest and exercise. We find that four or five sites dominate during rest in this ex vivo system. Remarkably, the quinol site in complex I (site I Q ) and the flavin site in complex II (site II F ) each account for about a quarter of the total measured rate of H 2 O 2 production. Site I F , site III Qo , and perhaps site E F in the β-oxidation pathway account for most of the remainder. Under conditions mimicking mild and intense aerobic exercise, total production is much less, and the low capacity site I F dominates. These results give novel insights into which mitochondrial sites may produce superoxide/H 2 O 2 in vivo .Ten mitochondrial sites of superoxide/H 2 O 2 generation are known, but their contributions in vivo are undefined. Results We assessed their rates ex vivo in conditions mimicking rest and exercise. Conclusion Sites I Q and II F generated half the signal at rest. During exercise, rates were lower, and site I F dominated. Significance Contributing sites ex vivo probably reflect those in vivo .
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“the assembly of these complexes in supercomplexes seems to regulate ROS production (Goncalves et al., 2015).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Goncalves et al., 2015
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Catalytic Coupling of Oxidative Phosphorylation, ATP Demand, and Reactive Oxygen Species Generation
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Wang, Y., Lilienfeldt, N., & Hekimi, S. (2024) · Physiological Reviews · doi:10.1152/physrev.00040.2023 · Cited by 88
Decreased mitochondrial metabolic requirements in fasting animals carry an oxidative cost
Salin, K., Villasevil, E. M., Anderson, G. J., Auer, S. K., Selman, C., Hartley, R. C., Mullen, W., Chinopoulos, C., & Metcalfe, N. B. (2018) · Functional Ecology · doi:10.1111/1365-2435.13125 · Cited by 79
Redox signalling and mitochondrial stress responses; lessons from inborn errors of metabolism
Olsen, R. K. J., Cornelius, N., & Gregersen, N. (2015) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-015-9861-5 · Cited by 83
A case of mistaken identity: are reactive oxygen species actually reactive sulfide species?
DeLeon, E. R., Gao, Y., Huang, E. S., Arif, M. S., Arora, N., Divietro, A., Patel, S., & Olson, K. R. (2016) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00455.2015 · Cited by 77
Cao, T., Fan, S., Zheng, D., Wang, G., Yu, Y. Q., Chen, R., Song, L., Fan, G., Zhang, Z., & Peng, T. (2019) · Basic Research in Cardiology · doi:10.1007/s00395-019-0726-1 · Cited by 73
Treatment of the Fluoroquinolone‐Associated Disability: The Pathobiochemical Implications
Michalak, K. P., Sobolewska-Włodarczyk, A., Włodarczyk, M., Sobolewska, J., Woźniak, P., & Sobolewski, B. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/8023935 · Cited by 76
Margaritelis, N. V., Cobley, J. N., Paschalis, V., Veskoukis, A. S., Theodorou, A. A., Kyparos, A., & Nikolaidis, M. G. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.12.011 · Cited by 74
Thirupathi, A., & Pinho, R. A. (2018) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-018-0633-1 · Cited by 75
How the brain fights fatty acids’ toxicity
Schönfeld, P., & Reiser, G. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105050 · Cited by 71
Production of superoxide/hydrogen peroxide by the mitochondrial 2-oxoadipate dehydrogenase complex
Goncalves, R. L. S., Bunik, V. I., & Brand, M. D. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.12.020 · Cited by 72
“In these experiments neither 2-aminoadipate nor 2-oxoadipate was added [28], so we cannot predict the contribution of site AF in vivo.”
BackgroundMethodInfluentialNitric oxide regulation of cellular metabolism: Adaptive tuning of cellular energy
Pappas, G., Wilkinson, M. L., & Gow, A. J. (2022) · Nitric Oxide · doi:10.1016/j.niox.2022.11.006 · Cited by 74
Gonçalves, R. L. S., Watson, M. A., Wong, H. S., Orr, A. L., & Brand, M. D. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101341 · Cited by 68
“3 mg of protein • ml) were incubated at 37 °C for 10min in “basic medium” (described below) [10].”
BackgroundMethodInfluentialSidlauskaite, E., Gibson, J. W., Megson, I. L., Whitfield, P. D., Tovmasyan, A. G., Batinic̈‐Haberle, I., Murphy, M. P., Moult, P. R., & Cobley, J. N. (2018) · Redox Biology · doi:10.1016/j.redox.2018.03.012 · Cited by 68
Mito-Nuclear Communication by Mitochondrial Metabolites and Its Regulation by B-Vitamins
Janssen, J. J. E., Grefte, S., Keijer, J., & de Boer, V. C. J. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00078 · Cited by 70
Poon, J., Zilka, O., & Pratt, D. A. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.0c06379 · Cited by 69
Endogenous and Exogenous Antioxidants in Skeletal Muscle Fatigue Development during Exercise
Supruniuk, E., Górski, J., & Chabowski, A. (2023) · Antioxidants · doi:10.3390/antiox12020501 · Cited by 72
“This was shown to be related to a transition to so-called state 3 respiration (ADP-stimulated oxidative phosphorylation) associated with a lower protonmotive force and the oxidation of ubiquinone pool, while site IF (with low-capacity to O2 production) was shown to be the major ROS contributor [37].”
BackgroundFang, J., Wong, H. S., & Brand, M. D. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101722 · Cited by 67
“Using isolated muscle mitochondria incubated in media mimicking the cytosol of resting skeletal muscle, use of endogenous reporters established that superoxide/hydrogen peroxide was produced mainly by sites IQ and IF of complex I, site IIF of complex II, and site IIIQo of complex III [5].”
MethodMitochondrial dynamics in exercise physiology
Tanaka, T., Nishimura, A., Nishiyama, K., Goto, T., Numaga‐Tomita, T., & Nishida, M. (2019) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-019-02258-3 · Cited by 67
Mitochondrial-Targeted Catalase
Dai, D., Chiao, Y. A., Martin, G. M., Marcinek, D. J., Basisty, N., Quarles, E. K., & Rabinovitch, P. S. (2017) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2016.12.015 · Cited by 65
Oxidative stress and aging: Learning from yeast lessons
Eleuthério, E. C. A., Brasil, A. D. A., França, M. B., de Almeida, D. S. G., Rona, G. B., & Magalhães, R. S. S. (2017) · Fungal Biology · doi:10.1016/j.funbio.2017.12.003 · Cited by 64
Oxidative metabolism and efficiency: the delicate balancing act of mitochondria
Bottje, W. G. (2018) · Poultry Science · doi:10.3382/ps/pey405 · Cited by 71
Yan, Y., Chang, L., Tian, H., Wang, L., Zhang, Y., Yang, T., Li, G., Hu, W., Shah, K., Chen, G., et al. (2018) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-018-0466-z · Cited by 60
Martínez‐Klimova, E., Aparicio‐Trejo, O. E., Gómez‐Sierra, T., Jiménez‐Uribe, A. P., Bellido, B., & Pedraza‐Chaverrí, J. (2020) · BioFactors · doi:10.1002/biof.1673 · Cited by 62
“Nevertheless, it should be remembered that the increase in ROS may also be the result of ETS' elements dysfunction, the increase in mitochondrial electron leak or the establishment of a vicious cycle of mitochondrial and NOXs ROS production increase.(39,106,109,117,118) Therefore, temporal studies of mitochondrial bio…”
BackgroundLi, Y., Zhou, Z.-H., Chen, M.-H., Yang, J., Leng, J., Cao, G.-S., Xin, G.-Z., Liu, L.-F., Kou, J.-P., Liu, B.-L., et al. (2016) · Antioxidants & Redox Signaling · doi:10.1089/ars.2015.6479 · Cited by 61
Thiol switches in mitochondria: operation and physiological relevance
Riemer, J., Schwarzländer, M., Conrad, M., & Herrmann, J. M. (2015) · Biological Chemistry · doi:10.1515/hsz-2014-0293 · Cited by 58
“For instance, while the respiratory chain is commonly viewed as the main generator of O2, isolated mitochondria have recently been reported to produce O2/H2O2 at much higher rates from 2-oxoacid dehydrogenase complexes than from complex I under certain conditions (Quinlan et al., 2014; Goncalves et al., 2015).”
BackgroundAntioxidant effect of exercise: Exploring the role of the mitochondrial complex I superassembly
Huertas, J. R., Fazazi, S. A., Hidalgo‐Gutiérrez, A., López, L. C., & Casuso, R. A. (2017) · Redox Biology · doi:10.1016/j.redox.2017.07.009 · Cited by 60
“Because ex vivo studies demonstrate that CI is the main source of mitochondrial ROS production under aerobic exercise conditions [9], our hypothesis states that the CI assembly into an SC may have a primary role in the antioxidant effects of endurance exercise.”
BackgroundAparicio‐Trejo, O. E., Tapia, E., Sánchez‐Lozada, L. G., & Pedraza‐Chaverrí, J. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.07.015 · Cited by 58
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“Aside from Nox enzymes, the mitochondrion is another main source of ROS in cisplatin-treated cells; in response, the mitochondrial enzyme SOD1 converts superoxide anions to harmless H2O2 and antagonizes potential oxidative damage in the mitochondrial intra-membrane space [21,55,56].”
BackgroundCommon and divergent molecular mechanisms of fasting and ketogenic diets
Paoli, A., Tinsley, G. M., Mattson, M. P., Vivo, I. D., Dhawan, R., & Moro, T. (2023) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2023.10.001 · Cited by 63
Mitochondrial dysfunction in metabolism and ageing: shared mechanisms and outcomes?
López‐Lluch, G., Hernández‐Camacho, J. D., Fernández‐Ayala, D. J. M., & Navas, P. (2018) · Biogerontology · doi:10.1007/s10522-018-9768-2 · Cited by 60
Kramer, P. A., Duan, J., Qian, W.-J., & Marcinek, D. J. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00347 · Cited by 54
Munro, D., & Pamenter, M. E. (2019) · Aging Cell · doi:10.1111/acel.13009 · Cited by 55
“Succinate is particularly effective at elevating superoxide forma‐ tion at sites IQ, IIF, and IIIQo, respectively, found in complexes I, II, and III (Brand, 2010; Goncalves et al., 2015).”
BackgroundInfluentialIntegration of superoxide formation and cristae morphology for mitochondrial redox signaling
Plecitá‐Hlavatá, L., & Ježek, P. (2016) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2016.09.010 · Cited by 57
Metadata
- Authors
- Goncalves, R. L. S., Quinlan, C. L., Perevoshchikova, I. V., Hey-Mogensen, M., & Brand, M. D.
- Affiliations
- Buck Institute for Research on Aging (US)
- Corresponding author
- Goncalves, Renata L.S.
- Perevoshchikova, Irina V.
- Brand, Martin D.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 290
- Issue
- 1
- Pages
- 209-227
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4281723
- OpenAlex
- W2087350238
- Cited by
- 329
- References
- 162
- Citations by year
- 2026: 15 · 2025: 17 · 2024: 23 · 2023: 30 · 2022: 40 · 2021: 30 · 2020: 33 · 2019: 39 · 2018: 27 · 2017: 34 · 2016: 20 · 2015: 21
- FWCI
- 10.24
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (TL1 AG032116)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
- Keywords
- superoxide production, hydrogen peroxide production, skeletal muscle mitochondria, mitochondrial electron transport chain, fatty acid beta-oxidation, physical activity, rest, reactive oxygen species, isolated mitochondria
- MeSH terms
- Animals, Female, Hydrogen Peroxide, Malates, Mitochondria, Muscle, Oligomycins, Oxygen Consumption, Physical Conditioning, Animal, Rest, Superoxides, Uncoupling Agents, Rats, Wistar, Muscle, Skeletal, Succinic Acid, Electron Transport Complex II, Electron Transport Complex I, Cytochromes b, Tissue Culture Techniques, Rats
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