Superoxide production by NADH:ubiquinone oxidoreductase (complex I) depends on the pH gradient across the mitochondrial inner membrane
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The relationship between protonmotive force and superoxide production by mitochondria is poorly understood. To address this issue, the rate of superoxide production from complex I of rat skeletal muscle mitochondria incubated under a variety of conditions was assessed. By far, the largest rate of superoxide production was from mitochondria respiring on succinate; this rate was almost abolished by rotenone or piericidin, indicating that superoxide production from complex I is large under conditions of reverse electron transport. The high rate of superoxide production by complex I could also be abolished by uncoupler, confirming that superoxide production is sensitive to protonmotive force. It was inhibited by nigericin, suggesting that it is more dependent on the pH gradient across the mitochondrial inner membrane than on the membrane potential. These effects were examined in detail, leading to the conclusions that the effect of protonmotive force was mostly direct, and not indirect through changes in the redox state of the ubiquinone pool, and that the production of superoxide by complex I during reverse electron transport was at least 3-fold more sensitive to the pH gradient than to the membrane potential.
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Under conditions of reverse electron transfer, inhibiting complex II lowers complex I-related ROS generation.
“Under these conditions inhibition of complex II leads to a reduction of complex I related ROS generation [15,16,19,20,24].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [20]
Complex II inhibitors that bind the dicarboxylate site or the Qp site attenuate ROS production when succinate is the prevalent substrate.
“The ROS production is also attenuated by complex II inhibitors that bind either to the dicarboxylate site or the Qp site if succinate is the prevalent substrate [15,16,19,20,24].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [20]
This mechanism is supported by several studies with isolated mitochondria.
“Such a mechanism is supported by several studies with isolated mitochondria [15,16,19,20,24].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [20]
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- Authors
- LAMBERT, A. J., & BRAND, M. D.
- Affiliations
- MRC Mitochondrial Biology Unit (GB)
- ORCID
- BRAND, Martin D.
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2004-08-24
- Volume
- 382
- Issue
- 2
- Pages
- 511-517
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1133807
- OpenAlex
- W2035127779
- Cited by
- 470
- References
- 52
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 14 · 2023: 16 · 2022: 16 · 2021: 27 · 2020: 15 · 2019: 24 · 2018: 26 · 2017: 20 · 2016: 19 · 2015: 31 · 2014: 28 · 2013: 26 · 2012: 28
- FWCI
- 7.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- superoxide production, complex I, mitochondrial respiration, proton motive force, pH gradient, inner mitochondrial membrane, reverse electron transfer, succinic acid, rotenone, piericidins, nigericin, membrane potential, skeletal muscle mitochondria, uncouplers
- MeSH terms
- Animals, Female, Hydrogen Peroxide, Hydrogen-Ion Concentration, Intracellular Membranes, Mitochondria, Mitochondria, Muscle, Superoxides, Rats, Wistar, Muscle, Skeletal, Electron Transport Complex I, Rats
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