Sites of superoxide and hydrogen peroxide production by muscle mitochondria assessed ex vivo under conditions mimicking rest and exercise

Goncalves, Renata L.S.; Quinlan, Casey L.; Perevoshchikova, Irina V.; Hey-Mogensen, Martin; Brand, Martin D.

doi:10.1074/jbc.m114.619072

Cited by 329Mitochondrial Function and PathologyRedox biology and oxidative stressExercise and Physiological Responses

Sites of superoxide and hydrogen peroxide production by muscle mitochondria assessed ex vivo under conditions mimicking rest and exercise

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Goncalves, Renata L.S., Quinlan, Casey L., Perevoshchikova, Irina V., Hey-Mogensen, Martin, Brand, Martin D.·2015·Journal of Biological Chemistry

DOI 10.1074/jbc.m114.619072PMC PMC4281723

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Abstract

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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Assembly of mitochondrial electron transport chain complexes in supercomplexes seems to regulate ROS production.
“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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Self-citation
Mitochondrial and myoplasmic [Ca2+] in single fibres from mouse limb muscles during repeated tetanic contractions
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Mitochondrial and myoplasmic [Ca2+] in single fibres from mouse limb muscles during repeated tetanic contractions
Bruton, J. D., Tavi, P., Aydin, J., Westerblad, H., & Lännergren, J. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2003.043927 · Cited by 63 · see citing works
Effect of dietary manipulations (fasting, hypocaloric feeding, and subsequent refeeding) on rat muscle energetics as assessed by nuclear magnetic resonance spectroscopy.
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Leucine oxidation in diabetes and starvation: Effects of ketone bodies on branched-chain amino acid oxidation in vitro
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Effect of endurance training on muscle tca cycle metabolism during exercise in humans
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Tissue spaces in rat heart, liver, and skeletal muscle in vivo
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Catalytic enzyme histochemistry and biochemical analysis of dihydroorotate dehydrogenase/oxidase and succinate dehydrogenase in mammalian tissues, cells and mitochondria
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Fructose 2,6-bisphosphate in rat skeletal muscle during contraction
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Free [ADP] and Aerobic Muscle Work Follow at Least Second Order Kinetics in Rat Gastrocnemius in Vivo
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Glutamine Metabolism in Skeletal Muscle of Glucocorticoid-Treated Rats
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Proline metabolism in isolated rat liver cells
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Validity of the digitonin method for metabolite compartmentation in isolated hepatocytes
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Role of NADP+-linked malic enzymes as regulators of the pool size of tricarboxylic acid-cycle intermediates in the perfused rat heart
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Bioenergetic changes during contraction and recovery in diabetic rat skeletal muscle
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Modifications by chronic intermittent hypoxia and drug treatment on skeletal muscle metabolism
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Characteristics of osmolarity-stimulated urea transport in rat IMCD
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Compartmentation of citrate in relation to the regulation of glycolysis and the mitochondrial transmembrane proton electrochemical potential gradient in isolated perfused rat heart
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Effects of carbonic anhydrase inhibitors on contraction, intracellular pH and energy‐rich phosphates of rat skeletal muscle.
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Free amino acids in muscle: effect of muscle fiber population and denervation
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Relationship between plasma and muscle concentrations of ketone bodies and free fatty acids in fed, starved and alloxan-diabetic states
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The Regulation of Skeletal Muscle Alanine and Glutamine Formation and Release in Experimental Chronic Uremia in the Rat
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Subcellular distribution of malate-aspartate cycle intermediates during normoxia and anoxia in the heart
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Incorporation and utilization of [3-13C]lactate and [1,2-13C]acetate by rat skeletal muscle
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Effects of sampling procedures on the contents of some intermediate metabolities of glycolysis in rat tissues.
Dale, R. A. (1965) · The Journal of Physiology · doi:10.1113/jphysiol.1965.sp007792 · Cited by 27 · see citing works
Role of glucocorticoids in increased muscle glutamine production in starvation
Tischler, M. E., Henriksen, E. J., & Cook, P. H. (1988) · Muscle & Nerve · doi:10.1002/mus.880110711 · Cited by 25 · see citing works
Osmolarity modulates K+ channel function on rat hippocampal interneurons but not CA1 pyramidal neurons.
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Regulation of branched-chain 2-oxo acid dehydrogenase activity during exercise
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Mitochondrial metabolism in different thyroid states
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The intracellular concentration of free magnesium in extensor digitorum longus muscles of the rat
MacDermott, M. (1990) · Experimental Physiology · doi:10.1113/expphysiol.1990.sp003458 · Cited by 24 · see citing works
Changes in volume densities and distribution of mitochondria in rat skeletal muscle after chronic hypoxia.
van Ekeren, G. J., Sengers, R. C. A., & Stadhouders, A. M. (1992) · Europe PMC (PubMed Central) · Cited by 24 · see citing works
Diphosphopyridine Nucleotide-linked Cytoplasmic Metabolites in Rat Leg Muscle in Situ during Contraction and Recovery
Sacktor, B., Wormser-Shavit, E., & White, J. I. (1965) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)97379-5 · Cited by 23 · see citing works
31P NMR quantitation of phosphorus metabolites in rat heart and skeletal muscle in vivo
Hitchins, S., Cieslar, J. H., & Dobson, G. P. (2001) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2001.281.2.h882 · Cited by 22 · see citing works
Effect of long-term caloric restriction and exercise on muscle bioenergetics and force development in rats
Horská, A., Brant, L. J., Ingram, D. K., Hansford, R. G., Roth, G. S., & Spencer, R. G. S. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.276.4.e766 · Cited by 22 · see citing works
Causes of fatigue in slow-twitch rat skeletal muscle during dynamic activity
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Dexamethasone impairs muscle energetics, studied by 31P NMR, in rats
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An acute decrease in TCA cycle intermediates does not affect aerobic energy delivery in contracting rat skeletal muscle
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The effect of starvation in the rat on metabolite concentrations in blood, liver and skeletal muscle
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Metabolic profiling of muscle contraction in lean compared with obese rodents
Thyfault, J. P., Cree, M. G., Tapscott, E. B., Bell, J. A., Koves, T. R., Ilkayeva, O., Wolfe, R. R., Dohm, G. L., & Muoio, D. M. (2010) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00093.2010 · Cited by 21 · see citing works
Effects in vivo of decreased plasma and intracellular muscle glutamine concentration on whole-body and hindquarter protein kinetics in rats
Damink, S. W. M. O., de Blaauw, I., Deutz, N. E. P., & Soeters, P. B. (1999) · Clinical Science · doi:10.1042/cs0960639 · Cited by 20 · see citing works
Regulation of alanine formation and release in rat muscle in vivo: effect of starvation and diabetes.
Ruderman, N. B., Schmahl, F. W., & Goodman, M. N. (1977) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1977.233.2.e109 · Cited by 20 · see citing works
α-Glycerophosphate metabolism in muscle under aerobic and hypoxic conditions
Peterson, R. D., Gaudin, D., Bocek, R. M., & Beatty, C. H. (1964) · American Journal of Physiology-Legacy Content · doi:10.1152/ajplegacy.1964.206.3.599 · Cited by 19 · see citing works
Metabolic Changes Induced by Ethanol in Muscle and Liver Tissue of the Rat in vivo.
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Effect of Osmolarity on Aldosterone Production by Rat Adrenal Glomerulosa Cells1
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Muscle glutamine production in diabetic ketoacidotic rats
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Concentrations of Selected Enzymes and Metabolites in Rat Skeletal Muscle: Effects of Food Restriction
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Compartmental distribution of amino acids during hemodialysis-induced hypoaminoacidemia
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Effects in vivo of decreased plasma and intracellular muscle glutamine concentration on whole-body and hindquarter protein kinetics in rats
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Mass spectrometric determination of HCO3− permeability and carbonic anhydrase activity in intact guinea‐pig colon epithelium
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The Redox State and the Concentration of Ketone Bodies in Tissues of Rats Fed Carbohydrate Free Diets
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Oxidative Stress
Sies, H., Berndt, C., & Jones, D. P. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-045037 · Cited by 3,520 · see citing works
ROS signalling in the biology of cancer
Moloney, J. N., & Cotter, T. G. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2017.05.023 · Cited by 1,983 · see citing works
From discoveries in ageing research to therapeutics for healthy ageing
Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019) · Nature · doi:10.1038/s41586-019-1365-2 · Cited by 1,389 · see citing works
Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling
Brand, M. D. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.04.001 · Cited by 1,063 · see citing works
ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection
Cadenas, S. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.01.024 · Cited by 819 · see citing works
The Redox Code
Jones, D. P., & Sies, H. (2015) · Antioxidants & Redox Signaling · doi:10.1089/ars.2015.6247 · Cited by 647 · see citing works
“Unlike the NADH sites, most of which have catalytic functions supporting energetics and metabolism, most protein thiols have noncatalytic functions, for example, protein folding, regulation of activity, control of macromolecular interactions, and directional trafficking (47).”
BackgroundInfluential
The Two Faces of Reactive Oxygen Species in Cancer
Reczek, C. R., & Chandel, N. S. (2017) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-041916-065808 · Cited by 602 · see citing works
“Signaling-associated ROS are produced from two main sources, the mitochondria and membranebound NADPH oxidases (NOXs) (Figure 1) (Brewer et al. 2015, Goncalves et al. 2015).”
Background
Role of mitochondrial reverse electron transport in ros signaling: Potential roles in health and disease
Scialò, F., Fernández-Ayala, D. J., & Sanz, A. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00428 · Cited by 517 · see citing works
“…and combination of substrates used to feed the RC. Experiments performed in vitro designed to mimic the cytosolic environment of the muscle (Goncalves et al., 2015) show that the main sites of ROS generation are respiratory complexes I (aka NADH:ubiquinone oxidoreductase, CI), II (aka…”
Background
Mitochondrial Oxidative Stress—A Causative Factor and Therapeutic Target in Many Diseases
Kowalczyk, P., Sulejczak, D., Kleczkowska, P., Bukowska‐Ośko, I., Kucia, M., Popiel, M., Wietrak, E., Kramkowski, K., Wrzosek, K., & Kaczyńska, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413384 · Cited by 528 · see citing works
“The main source of ROS formation in the mitochondrion, demonstrated in vitro, is electron leakage from respiratory complexes I, II, and III of the respiratory chain, mediating the one-electron reduction of oxygen to superoxide (O2) [14,16,17].”
Background
Production of superoxide and hydrogen peroxide from specific mitochondrial sites under different bioenergetic conditions
Wong, H. S., Dighe, P. A., Mezera, V., Monternier, P., & Brand, M. D. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r117.789271 · Cited by 478 · see citing works
“/H2O2 at different rates depending on the substrate being oxidized (38, 48).”
BackgroundInfluential
Impact of Oxidative Stress on Exercising Skeletal Muscle
Steinbacher, P., & Eckl, P. (2015) · Biomolecules · doi:10.3390/biom5020356 · Cited by 416 · see citing works
“Under conditions that mimic mild and intense aerobic exercise, total production is much less and the low capacity site IF dominates [20].”
Background
PGC-1α-mediated regulation of mitochondrial function and physiological implications
Halling, J. F., & Pilegaard, H. (2020) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2020-0005 · Cited by 418 · see citing works
“On the contrary, the substrate and pH conditions observed in muscle cells during exercise are associated with a reduction in ROS production from all known sites of superoxide and hydrogen peroxide production in mitochondria isolated from rat skeletal muscle (Goncalves et al., 2015).”
Background
Exercise‐induced oxidative stress: past, present and future
Powers, S. K., Radak, Z. O., & Ji, L. L. (2016) · The Journal of Physiology · doi:10.1113/jp270646 · Cited by 361 · see citing works
“Nonetheless, recent advances in the field indicate that mitochondria are not the dominant source of ROS in contracting skeletal muscle (Sakellariou et al. 2013; Goncalves et al. 2015) and that NADPH oxidase is likely to play a key role in contraction-induced production of ROS (Sakellariou et al.”
BackgroundInfluential
Control of mitochondrial superoxide production by reverse electron transport at complex I
Robb, E. L., Hall, A. R., Prime, T. A., Eaton, S. D., Szibor, M., Viscomi, C. F., James, A. M., & Murphy, M. P. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.003647 · Cited by 322 · see citing works
“(2, 7, 8), respiratory chain complex I is considered to be a major contributor (1).”
Background
Exercise Metabolism and Adaptation in Skeletal Muscle
Smith, J. A. B., Murach, K. A., Dyar, K. A., & Zierath, J. R. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00606-x · Cited by 342 · see citing works
ROS and RNS signalling: adaptive redox switches through oxidative/nitrosative protein modifications
Moldogazieva, N. T., Mokhosoev, I. M., Feldman, N. B., & Lutsenko, S. V. (2018) · Free Radical Research · doi:10.1080/10715762.2018.1457217 · Cited by 291 · see citing works
Calorie restriction as an intervention in ageing
López‐Lluch, G., & Navas, P. (2015) · The Journal of Physiology · doi:10.1113/jp270543 · Cited by 290 · see citing works
“As in the case of other regulators such as sirtuins, its effect on longevity has been observed in several organisms from yeast to mammals.”
Background
The path from mitochondrial <scp>ROS</scp> to aging runs through the mitochondrial permeability transition pore
Rottenberg, H., & Hoek, J. B. (2017) · Aging Cell · doi:10.1111/acel.12650 · Cited by 275 · see citing works
“…the sites, mechanisms, and rates of mitochondrial ROS production under different metabolic conditions (Figueira et al., 2013; Zorov et al., 2014; Goncalves et al., 2015 Brand, 2016), little effort was devoted to elucidating the routes by which mROS leave the mitochondria and reach the cytosol.”
Background
Physiological Signaling Functions of Reactive Oxygen Species in Stem Cells: From Flies to Man
Sinenko, S. A., Starkova, T. Y., Kuzmin, A. A., & Tomilin, A. N. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.714370 · Cited by 256 · see citing works
Role of reactive oxygen species in ultraviolet-induced photodamage of the skin
Wei, M., He, X., Liu, N., & Deng, H. (2024) · Cell Division · doi:10.1186/s13008-024-00107-z · Cited by 244 · see citing works
“Large part of endogenous ROS are produced from mitochondria, which contain 10 sites that are known to be capable of producing O 2 • − , and 1% of the consumed O 2 is used to produce O 2 • − [10].”
Background
Sulforaphane reactivates cellular antioxidant defense by inducing Nrf2/ARE/Prdx6 activity during aging and oxidative stress
Kubo, E., Chhunchha, B., Singh, P., Sasaki, H., & Singh, D. P. (2017) · Scientific Reports · doi:10.1038/s41598-017-14520-8 · Cited by 231 · see citing works
Suppressors of Superoxide-H 2 O 2 Production at Site I Q of Mitochondrial Complex I Protect against Stem Cell Hyperplasia and Ischemia-Reperfusion Injury
Brand, M. D., Goncalves, R. L. S., Orr, A. L., Vargas, L., Gerencser, A. A., Borch Jensen, M., Wang, Y. T., Melov, S., Turk, C. N., Matzen, J. T., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.08.012 · Cited by 228 · see citing works
“It is likely that mitochondria in resting skeletal muscle produce superoxide and/or H2O2 at significant rates from only four of these sites: site IQ (the site in respiratory complex I active during reverse electron transport, nominally the ubiquinone-binding site), site IIF (the flavin site of complex II), site IIIQo…”
Influential
Cytosolic ROS production by NADPH oxidase 2 regulates muscle glucose uptake during exercise
Henríquez-Olguin, C., Knudsen, J. R., Raun, S. H., Li, Z., Dalbram, E., Treebak, J. T., Sylow, L., Holmdahl, R., Richter, E. A., Jaimovich, E., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12523-9 · Cited by 228 · see citing works
Antioxidant supplements and endurance exercise: Current evidence and mechanistic insights
Mason, S. A., Trewin, A. J., Parker, L., & Wadley, G. D. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101471 · Cited by 226 · see citing works
“either at rest or during exercise/contraction [69,70].”
BackgroundInfluential
Heat stress impairs mitochondria functions and induces oxidative injury in broiler chickens1
Huang, C., Jiao, H., Song, Z., Zhao, J., Wang, X., & Lin, H. (2015) · Journal of Animal Science · doi:10.2527/jas.2014-8739 · Cited by 214 · see citing works
Mitochondrial Reactive Oxygen Species at the Heart of the Matter
Kornfeld, O. S., Hwang, S., Disatnik, M., Chen, C., Qvit, N., & Mochly‐Rosen, D. (2015) · Circulation Research · doi:10.1161/circresaha.116.305432 · Cited by 210 · see citing works
“For example, although the quinol site in complex I and the flavin site in complex II equally contribute to the majority of ROS production under basal conditions, the flavin site in complex I dominates ROS production under conditions that mimic aerobic exercise.(8) The dynamic nature of ROS production at the 10 mitocho…”
Background
A radical shift in perspective: mitochondria as regulators of reactive oxygen species
Munro, D., & Treberg, J. R. (2017) · Journal of Experimental Biology · doi:10.1242/jeb.132142 · Cited by 207 · see citing works
“…benchmarks for the physiological levels of %NAD(P)H in rat muscle mitochondria by comparing mixes of respiratory substrates and effectors mimicking the in vivo environment for three levels of physical activity: ‘rest’, ‘mild aerobic exercise’ and ‘intense aerobic exercise’ (Goncalves et al., 2015).”
BackgroundInfluential
Muscle metabolism and atrophy: let’s talk about sex
Rosa-Caldwell, M. E., & Greene, N. P. (2019) · Biology of Sex Differences · doi:10.1186/s13293-019-0257-3 · Cited by 202 · see citing works
“complex III within the mitochondria [182], and some”
Background
Redox Control of Skeletal Muscle Regeneration
Moal, E. L., Pialoux, V., Juban, G., Groussard, C., Zouhal, H., Chazaud, B., & Mounier, R. (2016) · Antioxidants and Redox Signaling · doi:10.1089/ars.2016.6782 · Cited by 197 · see citing works
“At least 10 sites that are capable of producing considerable amounts of ROS have been described (123).”
Contractile Defect Caused by Mutation in MYBPC3 Revealed under Conditions Optimized for Human PSC-Cardiomyocyte Function
Birket, M. J., Ribeiro, M. C., Kosmidis, G., Ward, D., Leitoguinho, A. R., van de Pol, V., Dambrot, C., Devalla, H. D., Davis, R. P., Mastroberardino, P. G., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.09.025 · Cited by 192 · see citing works
“Mitochondrial ROS production may also be lower as a result of the increased ATP turnover (Goncalves et al., 2015).”
Background
Integrating Mitochondrial Aerobic Metabolism into Ecology and Evolution
Koch, R. E., Buchanan, K. L., Casagrande, S., Crino, O. L., Dowling, D. K., Hill, G. E., Hood, W. R., McKenzie, M., Mariette, M. M., Noble, D. W. A., et al. (2021) · Trends in Ecology & Evolution · doi:10.1016/j.tree.2020.12.006 · Cited by 190 · see citing works
Mitochondrial Antioxidants and the Maintenance of Cellular Hydrogen Peroxide Levels
Mailloux, R. J. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/7857251 · Cited by 189 · see citing works
“Conditions that mimic rest or exercise in the muscle have been shown to dictate which sites form the most ROS in muscle mitochondria, which can affect how much H2O2 is released into the extramitochondrial space [15].”
Background
Metabolism of hydrogen sulfide (H2S) and Production of Reactive Sulfur Species (RSS) by superoxide dismutase
Olson, K. R., Gao, Y., Arif, F., Arora, K., Patel, S., DeLeon, E. R., Sutton, T. R., Feelisch, M., Cortese-Krott, M. M., & Straub, K. D. (2017) · Redox Biology · doi:10.1016/j.redox.2017.11.009 · Cited by 176 · see citing works
Exercise-Stimulated ROS Sensitive Signaling Pathways in Skeletal Muscle
Bouvière, J., Fortunato, R. S., Dupuy, C., Werneck‐de‐Castro, J. P., de Carvalho, D. P., & Louzada, R. A. N. (2021) · Antioxidants · doi:10.3390/antiox10040537 · Cited by 175 · see citing works
“However, during exercise, the mitochondria operate at state 3 (which is also known as the maximal ADP stimulated respiration) where O2 generation is lower [14], even when either succinate or pyruvate/malate are used as a substrate [27,28].”
Background
Catalase as a sulfide-sulfur oxido-reductase: An ancient (and modern?) regulator of reactive sulfur species (RSS)
Olson, K. R., Gao, Y., DeLeon, E. R., Arif, M. S., Arif, F., Arora, N., & Straub, K. D. (2017) · Redox Biology · doi:10.1016/j.redox.2017.02.021 · Cited by 151 · see citing works
“However, because catalase appears to have appeared in evolution long before oxygen was present and at a time when RSS were more likely to be involved in cellular metabolism [1], (also see discussion), we wondered if catalase could also dismutate persulfide, i.e.;”
Background
Metabolic reprogramming, oxidative stress, and pulmonary hypertension
Pokharel, M. D., Marciano, D. P., Fu, P., Franco, M. C., Unwalla, H. J., Tieu, K., Fineman, J. R., Wang, T., & Black, S. M. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102797 · Cited by 151 · see citing works
Oxidative Phosphorylation: A Target for Novel Therapeutic Strategies Against Ovarian Cancer
Nayak, A. P., Kapur, A., Barroilhet, L. M., & Patankar, M. S. (2018) · Cancers · doi:10.3390/cancers10090337 · Cited by 146 · see citing works
“The primary source of superoxide anions is the electron transport chain in the mitochondria [88,89].”
Background
Redox Regulation via Glutaredoxin-1 and Protein S -Glutathionylation
Matsui, R., Ferrán, B., Oh, A., Croteau, D., Shao, D., Han, J., Pimentel, D. R., & Bachschmid, M. M. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7963 · Cited by 139 · see citing works
“Predominant fatty acid oxidation can generate conditions of a highly reduced ubi-quinone pool combined with low succinate levels (perturbed anaplerosis), leading to an electron leak at complex II (61) and oxidant generation.”
Intracellular Sources of ROS/H2O2 in Health and Neurodegeneration: Spotlight on Endoplasmic Reticulum
Konno, T., Melo, E. P., Chambers, J. E., & Avezov, E. (2021) · Cells · doi:10.3390/cells10020233 · Cited by 140 · see citing works
“To date, eleven ETC-related enzymes have been identified as the source of ROS in mitochondria [77,78].”
Background
Mitochondrial ROS regulate oxidative damage and mitophagy but not age-related muscle fiber atrophy
Sakellariou, G. K., Pearson, T., Lightfoot, A. P., Nye, G. A., Wells, N., Giakoumaki, I. I., Vasilaki, A., Griffiths, R. D., Jackson, M. J., & McArdle, A. (2016) · Scientific Reports · doi:10.1038/srep33944 · Cited by 133 · see citing works
Exercise and mitochondrial dynamics: keeping in shape with ROS and AMPK
Trewin, A., Berry, B., & Wojtovich, A. (2018) · Antioxidants · doi:10.3390/antiox7010007 · Cited by 129 · see citing works
“Increased ROS occurs mostly from non-mitochondrial sources during contractile activity such as NADPH oxidases and xanthine oxidase [17,133,134], and mitochondria are likely a primary source of O2• generation in the post exercise period [53].”
Background
Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice
Campbell, M. D., Duan, J., Samuelson, A. T., Gaffrey, M. J., Merrihew, G. E., Egertson, J. D., Wang, L., Bammler, T. K., Moore, R. J., White, C. C., et al. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.12.031 · Cited by 134 · see citing works
“In addition to their role in ATP production, mitochondria are also a significant source of superoxide from multiple sites within the electron transport system [10].”
Background
Mitochondrial proton leaks and uncoupling proteins
Nicholls, D. G. (2021) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2021.148428 · Cited by 133 · see citing works
Redox basis of exercise physiology
Margaritelis, N. V., Paschalis, V., Theodorou, A. A., Kyparos, A., & Nikolaidis, M. G. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101499 · Cited by 129 · see citing works
“Given that the studies in redox bioenergetics specifically focused on physical activity are scarce [154], selected mechanistic information is derived from other scientific fields.”
BackgroundInfluential
Riding the tiger – physiological and pathological effects of superoxide and hydrogen peroxide generated in the mitochondrial matrix
Brand, M. D. (2020) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2020.1828258 · Cited by 123 · see citing works
Influence of vitamin C and vitamin E on redox signaling: implications for exercise adaptations
Cobley, J. N., McHardy, H., Morton, J. P., Nikolaidis, M. G., & Close, G. L. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.03.018 · Cited by 118 · see citing works
“There are several sources of superoxide in skeletal muscle, including: mitochondrial electr on 151 transport chain complex I and III, NADPH oxidases, dual oxidases, xanthine oxidase, 152 uncoupled NOS isoforms, phospholipases and lipoxyge nas s [57-59].”
Background
Resistance training to improve type 2 diabetes: working toward a prescription for the future
Pesta, D. H., Goncalves, R. L. S., Madiraju, A. K., Strasser, B., & Sparks, L. M. (2017) · Nutrition & Metabolism · doi:10.1186/s12986-017-0173-7 · Cited by 120 · see citing works
Thermal tolerance and thermal sensitivity of heart mitochondria: Mitochondrial integrity and ROS production
Christen, F., Desrosiers, V., Cyr, B.-A. D., Vandenberg, G. W., François, N. R. L., Tardif, J., Dufresne, F., Lamarre, S. G., & Blier, P. U. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.12.037 · Cited by 116 · see citing works
Individuals with higher metabolic rates have lower levels of reactive oxygen species in vivo
Salin, K., Auer, S. K., Rudolf, A. M., Anderson, G. J., Cairns, A. G., Mullen, W., Hartley, R. C., Selman, C., & Metcalfe, N. B. (2015) · Biology Letters · doi:10.1098/rsbl.2015.0538 · Cited by 114 · see citing works
“This is especially true when examining among-individual variation in mitochondrial traits, given that the in vitro conditions standardize the mitochondrial environment among individuals, which may hide the actual sources of variability in the relationship between oxygen consumption in vivo and mitochondrial ROS produc…”
Background
Spatial and temporal control of mitochondrial H2O2 release in intact human cells
Hoehne, M. N., Jacobs, L. H. C., Lapacz, K. J., Calabrese, G., Murschall, L. M., Marker, T., Kaul, H., Trifunović, A., Morgan, B., Fricker, M. D., et al. (2022) · The EMBO Journal · doi:10.15252/embj.2021109169 · Cited by 103 · see citing works
Mitochondrial Cristae Morphology Reflecting Metabolism, Superoxide Formation, Redox Homeostasis, and Pathology
Ježek, P., Jabůrek, M., Holendová, B., Engstová, H., & Dlasková, A. (2023) · Antioxidants and Redox Signaling · doi:10.1089/ars.2022.0173 · Cited by 111 · see citing works
“B.5), matrix DH complexes of 2-oxoglutarate DH (OGDH), pyruvate DH (PDH), branched-chain 2-oxoacid DH (BCKADH), and 2-oxoadipate (OADH) were also reported to produce superoxide in a forward but not reverse reactions (consuming NADH), as evidenced experimentally by studies of isolated mitochondria (Brand, 2016; Quinlan…”
BackgroundInfluential
Exercise increases mitochondrial complex I activity and DRP1 expression in the brains of aged mice
Gusdon, A. M., Callio, J., Distéfano, G., O'Doherty, R. M., Goodpaster, B. H., Coen, P. M., & Chu, C. T. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.01.013 · Cited by 109 · see citing works
“In situ ROS production during exercise is likely much lower given the presence of ADP and reduced membrane potential during active ATP generation (Goncalves et al., 2014).”
Background
The Endocannabinoid System and Physical Exercise
Matei, D., Trofin, D., Iordan, D. A., Onu, I., Condurache, I., Ionițe, C., & Buculei, I. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24031989 · Cited by 118 · see citing works
“Physical exercise (PE) is recognized as an important component of a healthy lifestyle, and the recommendation is 30 min of exercise training per day with moderate intensity, which is considered to reduce the risk of cardiovascular events [1].”
Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity
López-Lluch, G. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.12.005 · Cited by 103 · see citing works
Muscle redox signalling pathways in exercise. Role of antioxidants
Mason, S. A., Morrison, D., McConell, G. K., & Wadley, G. D. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.02.022 · Cited by 103 · see citing works
Mitochondrial and cytosolic sources of hydrogen peroxide in resting C2C12 myoblasts
Wong, H. S., Benoit, B., & Brand, M. D. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.10.448 · Cited by 102 · see citing works
The exceptional longevity of the naked mole‐rat may be explained by mitochondrial antioxidant defenses
Munro, D., Baldy, C., Pamenter, M. E., & Treberg, J. R. (2019) · Aging Cell · doi:10.1111/acel.12916 · Cited by 99 · see citing works
Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel
Murphy, M. P., & Chouchani, E. T. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-01004-8 · Cited by 99 · see citing works
The mitochondria-targeted antioxidant MitoQ, attenuates exercise-induced mitochondrial DNA damage
Williamson, J., Hughes, C., Cobley, J. N., & Davison, G. W. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101673 · Cited by 100 · see citing works
“mitochondria generate the greatest amount of O2⋅-/H2O2 at rest [6,67, 81], and as a result, it could be hypothesised that chronic MitoQ supplementation would have altered quiescent mitochondrial and/or nuclear DNA damage.”
Background
Exercise redox biochemistry: Conceptual, methodological and technical recommendations
Cobley, J. N., Close, G. L., Bailey, D. M., & Davison, G. W. (2017) · Redox Biology · doi:10.1016/j.redox.2017.03.022 · Cited by 96 · see citing works
“example, principal O2 generators switch from mitochondria at rest [141,142] to NOX isoforms during exercise (at least during shortduration exercise) in skeletal muscle [143,144].”
Background
The mitochondrial permeability transition: Nexus of aging, disease and longevity
Rottenberg, H., & Hoek, J. B. (2021) · Cells · doi:10.3390/cells10010079 · Cited by 94 · see citing works
Sepsis-induced myocardial dysfunction: the role of mitochondrial dysfunction
Yang, H., & Zhang, Z. (2021) · Inflammation Research · doi:10.1007/s00011-021-01447-0 · Cited by 91 · see citing works
Mitochondrial free radical overproduction due to respiratory chain impairment in the brain of a mouse model of Rett syndrome: protective effect of CNF1
Filippis, B. D., Valenti, D., Lidia de, B. A. R. I., Rasmo, D. D., Musto, M., Fabbri, A., Ricceri, L., Fiorentini, C., Laviola, G., & Vacca, R. A. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.02.014 · Cited by 90 · see citing works
“The further addition of MALO, the inhibitor of the flavin site of complex II [40], completely inhibited H2O2 production (Fig.”
Background
Hydrogen sulfide, reactive sulfur species and coping with reactive oxygen species
Olson, K. R. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.01.020 · Cited by 87 · see citing works
Redox signaling in the pancreas in health and disease
Sastre, J., Pérez, S., Sabater-Orti, L., & Rius‐Pérez, S. (2024) · Physiological Reviews · doi:10.1152/physrev.00044.2023 · Cited by 92 · see citing works
The thioredoxin and glutathione-dependent H2O2 consumption pathways in muscle mitochondria: Involvement in H2O2 metabolism and consequence to H2O2 efflux assays
Munro, D., Banh, S., Sotiri, E., Tamanna, N., & Treberg, J. R. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.04.014 · Cited by 83 · see citing works
Catalytic Coupling of Oxidative Phosphorylation, ATP Demand, and Reactive Oxygen Species Generation
Bazil, J. N., Beard, D. A., & Vinnakota, K. C. (2016) · Biophysical Journal · doi:10.1016/j.bpj.2015.09.036 · Cited by 81 · see citing works
Understanding coenzyme Q
Wang, Y., Lilienfeldt, N., & Hekimi, S. (2024) · Physiological Reviews · doi:10.1152/physrev.00040.2023 · Cited by 83 · see citing works
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 · see citing works
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 78 · see citing works
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 · see citing works
Increased calpain-1 in mitochondria induces dilated heart failure in mice: role of mitochondrial superoxide anion
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 · see citing works
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 73 · see citing works
Principles for integrating reactive species into in vivo biological processes: Examples from exercise physiology
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 71 · see citing works
Effects of reactive oxygen species and interplay of antioxidants during physical exercise in skeletal muscles
Thirupathi, A., & Pinho, R. A. (2018) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-018-0633-1 · Cited by 73 · see citing works
How the brain fights fatty acids’ toxicity
Schönfeld, P., & Reiser, G. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105050 · Cited by 70 · see citing works
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 70 · see citing works
“In these experiments neither 2-aminoadipate nor 2-oxoadipate was added [28], so we cannot predict the contribution of site AF in vivo.”
BackgroundMethodInfluential
Nitric 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 71 · see citing works
The use of site-specific suppressors to measure the relative contributions of different mitochondrial sites to skeletal muscle superoxide and hydrogen peroxide production
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 · see citing works
“3 mg of protein • ml) were incubated at 37 °C for 10min in “basic medium” (described below) [10].”
BackgroundMethodInfluential
Mitochondrial ROS cause motor deficits induced by synaptic inactivity: Implications for synapse pruning
Sidlauskaite, 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 · see citing works
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 68 · see citing works
Potent Ferroptosis Inhibitors Can Catalyze the Cross-Dismutation of Phospholipid-Derived Peroxyl Radicals and Hydroperoxyl Radicals
Poon, J., Zilka, O., & Pratt, D. A. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.0c06379 · Cited by 66 · see citing works
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 70 · see citing works
“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].”
Background
Production of superoxide and hydrogen peroxide in the mitochondrial matrix is dominated by site IQ of complex I in diverse cell lines
Fang, J., Wong, H. S., & Brand, M. D. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101722 · Cited by 64 · see citing works
“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].”
Method
Mitochondrial 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 66 · see citing works
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 62 · see citing works
Oxidative stress and aging: Learning from yeast lessons
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Characterization and suppression of mitochondrial production of superoxide and hydrogen peroxide under near-physiological conditions
Brand, M. D., Quinlan, C. L., Goncalves, R. L. S., Perevoshchikova, I. V., Treberg, J. R., Hey‐Mogensen, M., Gerencser, A. A., & Orr, A. L. (2014) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2014.05.224
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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.
ORCID: Goncalves, Renata L.S.
Quinlan, Casey L.
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)
DOI: 10.1074/jbc.m114.619072
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 2102 d)
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 › Rehabilitation › 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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Sites of superoxide and hydrogen peroxide production by muscle mitochondria assessed ex vivo under conditions mimicking rest and exercise

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