High rates of superoxide production in skeletal-muscle mitochondria respiring on both complex I- and complex II-linked substrates
Abstract
Despite the considerable interest in superoxide as a potential cause of pathology, the mechanisms of its deleterious production by mitochondria remain poorly understood. Previous studies in purified mitochondria have found that the highest rates of superoxide production are observed with succinate-driven reverse-electron transfer through complex I, although the physiological importance of this pathway is disputed because it necessitates high concentrations of succinate and is thought not to occur when NAD is in the reduced state. However, very few studies have examined the rates of superoxide production with mitochondria respiring on both NADH-linked (e.g. glutamate) and complex II-linked substrates. In the present study, we find that the rates of superoxide production (measured indirectly as H2O2) with glutamate+succinate (∼1100 pmol of H2O2·min−1·mg−1) were unexpectedly much higher than with succinate (∼400 pmol of H2O2·min−1·mg−1) or glutamate (∼80 pmol of H2O2·min−1·mg−1) alone. Superoxide production with glutamate+succinate remained high even at low substrate concentrations (<1 mM), was decreased by rotenone and was completely eliminated by FCCP (carbonyl cyanide p-trifluoromethoxyphenylhydrazone), indicating that it must in large part originate from reverse-electron transfer through complex I. Similar results were obtained when glutamate was replaced with pyruvate, α-ketoglutarate or palmitoyl carnitine. In contrast, superoxide production was consistently lowered by the addition of malate (malate+succinate ∼30 pmol of H2O2·min−1·mg−1). We propose that the inhibitory action of malate on superoxide production can be explained by oxaloacetate inhibition of complex II. In summary, the present results indicate that reverse-electron transfer-mediated superoxide production can occur under physiologically realistic substrate conditions and suggest that oxaloacetate inhibition of complex II may be an adaptive mechanism to minimize this.
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Malate reduces succinate-dependent ROS formation via accumulation of oxaloacetate that occurs unless acetyl-CoA is available.
“They have proposed that the reduction of the succinate-dependent ROS formation by malate is due to an accumulation of oxaloacetate that occurs unless acetyl-CoA is available.”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [23]
Different NADH-generating substrates have opposing effects on ROS generation.
“other studies demonstrated that different NADH-generating substrates have an opposing effect on ROS generation [23,35,108]”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [23]
Oxaloacetate inhibition of complex II has developed as a mechanism to minimize RET-mediated superoxide production.
“Furthermore, it can be concluded that the oxaloacetate inhibition of complex II has developed as a mechanism to minimize RET-mediated superoxide production [23].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [23]
The differential contribution of TCA cycle enzymes and the conditional removal of oxaloacetate are key factors controlling succinate-dependent ROS generation.
“it was suggested by Muller et al. that the differential contribution of TCA cycle enzymes and the conditional removal of the endogenous complex II inhibitor oxaloacetate are key factors that control succinate-dependent ROS generation [23].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [23]
A high rate of ROS production is observed when NADH-generating substrates and succinate are supplied together to isolated mitochondria.
“A high rate of ROS production is also observed when NADH-generating substrates and succinate are concomitantly supplied to isolated mitochondria [21,23,34,35].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [23]
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- Authors
- Muller, F. L., Liu, Y., Abdul-Ghani, M. A., Lustgarten, M. S., Bhattacharya, A., Jang, Y. C., & Van Remmen, H.
- Affiliations
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, Texas Research Park Campus, 15355 Lambda Drive, San Antonio, TX 78229-3900, U.S.A.
- The University of Texas at San Antonio Health Science Center (US)
- South Texas Veterans Health Care System (US)
- Corresponding author
- Bhattacharya, Arunabh
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2007-12-21
- Volume
- 409
- Issue
- 2
- Pages
- 491-499
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W2133593669
- Cited by
- 150
- References
- 59
- Citations by year
- 2025: 4 · 2024: 2 · 2023: 6 · 2022: 3 · 2021: 6 · 2020: 7 · 2019: 6 · 2018: 7 · 2017: 9 · 2016: 7 · 2015: 9 · 2014: 11 · 2013: 9 · 2012: 16
- FWCI
- 4.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (5T3 AG 021890 02, 1P30- AG13319, P01 AG19316, P01AG020591, P01AG019316, T32AG021890, P30AG013319)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Keywords
- superoxide production, skeletal muscle mitochondria, reverse electron transfer, complex I, complex II, succinic acid, glutamate, hydrogen peroxide, malate, rotenone, FCCP, pyruvate, alpha-ketoglutarate, palmitoylcarnitine
- MeSH terms
- Animals, Dose-Response Relationship, Drug, Malates, Mice, Inbred C57BL, Mitochondria, Muscle, NAD, Superoxides, Muscle, Skeletal, Glutamic Acid, Succinic Acid, Electron Transport Complex II, Electron Transport Complex I, Mice, Oxaloacetic Acid
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