Production of Reactive Oxygen Species by Mitochondria
Open accessAbstract
The mitochondrial respiratory chain is a major source of reactive oxygen species (ROS) under pathological conditions including myocardial ischemia and reperfusion. Limitation of electron transport by the inhibitor rotenone immediately before ischemia decreases the production of ROS in cardiac myocytes and reduces damage to mitochondria. We asked if ROS generation by intact mitochondria during the oxidation of complex I substrates (glutamate, pyruvate/malate) occurred from complex I or III. ROS production by mitochondria of Sprague-Dawley rat hearts and corresponding submitochondrial particles was studied. ROS were measured as H2O2 using the amplex red assay. In mitochondria oxidizing complex I substrates, rotenone inhibition did not increase H2O2. Oxidation of complex I or II substrates in the presence of antimycin A markedly increased H2O2. Rotenone prevented antimycin A-induced H2O2 production in mitochondria with complex I substrates but not with complex II substrates. Catalase scavenged H2O2. In contrast to intact mitochondria, blockade of complex I with rotenone markedly increased H2O2 production from submitochondrial particles oxidizing the complex I substrate NADH. ROS are produced from complex I by the NADH dehydrogenase located in the matrix side of the inner membrane and are dissipated in mitochondria by matrix antioxidant defense. However, in submitochondrial particles devoid of antioxidant defense ROS from complex I are available for detection. In mitochondria, complex III is the principal site for ROS generation during the oxidation of complex I substrates, and rotenone protects by limiting electron flow into complex III.
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Antimycin A inhibition of complex III leads to formation of toxic ROS.
“Moreover, toxic ROS are formed52.”
From Stimulation of superoxide production increases fungicidal action of miconazole against Candida albicans biofilms (2016) · cites this paper as [52]
The electron transport chain in the mitochondria can be a major source of superoxide production.
“The electron transport chain in the mitochondria can be a major source of superoxide production [46,47].”
From Asbestos and Iron (2023) · cites this paper as [46]
In coupled mitochondria and submitochondrial particles, high ROS production with saturating succinate is largely attributable to complex I via reverse electron transfer from complex II, because it is sensitive to complex I inhibitors, requires high membrane potential, and does not occur in uncoupled submitochondrial particles.
“In coupled mitochondria and SMP, high ROS production is observed under these conditions, but this can be largely attributed to complex I due to reverse electron transfer from complex II, since (i) it is sensitive to complex I inhibitors like rotenone [18][19][20]24,91,92], (ii) requires a high membrane potential, i.e. is sensitive to uncouplers and ionophores [15,[18][19][20]91] or ADP (that”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [93]
In the IMS, leaked electrons react with O2 to generate ROS, which reach the cytosol.
“In the IMS, leaked electrons react with O2 to generate ROS, which reach the cytosol [30,109,121,125,423].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [423]
Although nonmitochondrial sources of ROS exist during ischemia, the majority of ROS are likely derived from the mitochondrial respiratory complexes.
“Although nonmitochondrial sources of ROS exist during ischemia [e.g., NAD(P)H oxidase (141, 188, 328) and xanthine oxidase (25) in vasculature], the majority of ROS are likely derived from the mitochondrial respiratory complexes, as shown by the damage to respiratory complexes (212, 213, 245) and the effect of mitochondrial inhibitors (5, 28, 71, 81–86).”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [82]
Rotenone or amobarbital given just before the onset of cardiac ischemia resulted in improved oxidative phosphorylation and retention of cytochrome c in mitochondria isolated during ischemia or on reperfusion.
“Rotenone or amobarbital (a reversible inhibitor of complex I) given just before the onset of cardiac ischemia resulted in improved oxidative phosphorylation and retention of cytochrome c in mitochondria isolated during ischemia or on reperfusion (82, 85).”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [82]
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- Authors
- Chen, Q., Vazquez, E. J., Moghaddas, S., Hoppel, C. L., & Lesnefsky, E. J.
- Affiliations
- Xuzhou Medical College (CN)
- Louis Stokes Cleveland VA Medical Center (US)
- Corresponding author
- Lesnefsky, Edward J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-09
- Volume
- 278
- Issue
- 38
- Pages
- 36027-36031
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2026525843
- Cited by
- 1,616
- References
- 39
- Citations by year
- 2026: 35 · 2025: 62 · 2024: 57 · 2023: 43 · 2022: 68 · 2021: 84 · 2020: 81 · 2019: 79 · 2018: 69 · 2017: 82 · 2016: 86 · 2015: 98 · 2014: 92 · 2013: 75 · 2012: 87
- FWCI
- 19.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5k04ag000676-05)
- National Institute on Aging (1P0 AG15885, 1K04 AG-00676)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- reactive oxygen species, mitochondrial respiratory chain, complex I, cytochrome bc1 complex, rotenone, antimycin A, hydrogen peroxide, myocardial ischemia-reperfusion injury, NADH dehydrogenase, submitochondrial particles, catalase, glutamate oxidation
- MeSH terms
- Animals, Antioxidants, Binding Sites, Catalase, Electron Transport, Electrons, Hydrogen Peroxide, Ischemia, Male, Mitochondria, Models, Biological, Myocardium, NAD, NADH Dehydrogenase, Oxygen, Phosphorylation, Rotenone, Electron Transport Complex III, Reperfusion Injury, Rats, Sprague-Dawley, Reactive Oxygen Species, Succinic Acid, Myocytes, Cardiac, Rats
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