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The Mechanism of Mitochondrial Superoxide Production by the Cytochrome bc1 Complex
Open accessAbstract
Production of reactive oxygen species (ROS) by the mitochondrial respiratory chain is considered to be one of the major causes of degenerative processes associated with oxidative stress. Mitochondrial ROS has also been shown to be involved in cellular signaling. It is generally assumed that ubisemiquinone formed at the ubiquinol oxidation center of the cytochrome bc(1) complex is one of two sources of electrons for superoxide formation in mitochondria. Here we show that superoxide formation at the ubiquinol oxidation center of the membrane-bound or purified cytochrome bc(1) complex is stimulated by the presence of oxidized ubiquinone indicating that in a reverse reaction the electron is transferred onto oxygen from reduced cytochrome b(L) via ubiquinone rather than during the forward ubiquinone cycle reaction. In fact, from mechanistic studies it seems unlikely that during normal catalysis the ubisemiquinone intermediate reaches significant occupancies at the ubiquinol oxidation site. We conclude that cytochrome bc(1) complex-linked ROS production is primarily promoted by a partially oxidized rather than by a fully reduced ubiquinone pool. The resulting mechanism of ROS production offers a straightforward explanation of how the redox state of the ubiquinone pool could play a central role in mitochondrial redox signaling.
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“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 [32]
In the citing paper
“This ROS-promoting effect of complex II inhibitors can be related to a partially oxidized Q-pool that maximizes ROS production by complex III upon antimycin inhibition [25,32,33].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [32]
In the citing paper
“This can be explained by an increased oxidation of the Q-pool, since it was shown that the superoxide generation at the Q o site is maximal at intermediate reduction states of the ubiquinone pool if the Q i site is blocked by antimycin A [25,32,33].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [32]
In the citing paper
“Under these specific conditions, an intermediate succinate concentration/complex II activity results in an intermediate reduction of the Q-pool that favors superoxide production by complex III [32].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [32]
In the citing paper
“Mitochondrial cytochrome bc1 (complex III) inhibition is a major source of intracellular ROS generation [59].”
From Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant Candida auris (2024) · cites this paper as [59]
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Fridovich (1978) · doi:10.1126/science.210504 · Cited by 3,329
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Production of Reactive Oxygen Species by Mitochondria
Chen, Q., Vazquez, E. J., Moghaddas, S., Hoppel, C. L., & Lesnefsky, E. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304854200 · Cited by 1,616
Neurodegenerative diseases and oxidative stress
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Role of ubiquinone in the mitochondrial generation of hydrogen peroxide
Boveris, A., Cadenas, E., & Stoppani, A. O. M. (1976) · Biochemical Journal · doi:10.1042/bj1560435 · Cited by 655
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Are reactive oxygen species involved in Alzheimer's disease?
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The sites and topology of mitochondrial superoxide production
Brand, M. D. (2010) · Experimental Gerontology · doi:10.1016/j.exger.2010.01.003 · Cited by 1,217
Mitochondria and reactive oxygen species
Kowaltowski, A. J., de Souza-Pinto, N. C., Castilho, R. F., & Vercesi, A. E. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.05.004 · Cited by 1,162
Brand, M. D. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.04.001 · Cited by 1,063
Scharping, N. E., Rivadeneira, D. B., Menk, A. V., Vignali, P. D. A., Ford, B. R., Rittenhouse, N. L., Peralta, R., Wang, Y., Wang, Y., DePeaux, K., et al. (2021) · Nature Immunology · doi:10.1038/s41590-020-00834-9 · Cited by 897
Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease
Trist, B. G., Hare, D. J., & Double, K. L. (2019) · Aging Cell · doi:10.1111/acel.13031 · Cited by 778
Metadata
- Authors
- Dröse, S., & Brandt, U.
- Affiliations
- Goethe University Frankfurt (DE)
- Corresponding author
- Brandt, Ulrich
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 283
- Issue
- 31
- Pages
- 21649-21654
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1982085892
- Cited by
- 386
- References
- 35
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 19 · 2023: 10 · 2022: 11 · 2021: 21 · 2020: 22 · 2019: 14 · 2018: 27 · 2017: 22 · 2016: 29 · 2015: 24 · 2014: 24 · 2013: 22 · 2012: 27
- FWCI
- 12.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft ((EXC 115).)
- 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 › Photosynthetic Processes and Mechanisms
- Keywords
- cytochrome bc1 complex, mitochondrial superoxide production, reactive oxygen species, ubisemiquinone, electron transfer to oxygen, mitochondrial respiratory chain, oxidative stress, mitochondrial redox signaling
- MeSH terms
- Animals, Catalysis, Cattle, Dose-Response Relationship, Drug, Electron Transport, Mitochondria, Models, Biological, Molecular Conformation, Oxidation-Reduction, Oxidoreductases, Oxygen, Superoxides, Electron Transport Complex III, Ubiquinone, Reactive Oxygen Species
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