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The Mechanism of Superoxide Production by the Antimycin-inhibited Mitochondrial Q-cycle
Open accessAbstract
Superoxide production from antimycin-inhibited complex III in isolated mitochondria first increased to a maximum then decreased as substrate supply was modulated in three different ways. In each case, superoxide production had a similar bell-shaped relationship to the reduction state of cytochrome b(566), suggesting that superoxide production peaks at intermediate Q-reduction state because it comes from a semiquinone in the outer quinone-binding site in complex III (Q(o)). Imposition of a membrane potential changed the relationships between superoxide production and b(566) reduction and between b(562) and b(566) redox states, suggesting that b(562) reduction also affects semiquinone concentration and superoxide production. To assess whether this behavior was consistent with the Q-cycle mechanism of complex III, we generated a kinetic model of the antimycin-inhibited Q(o) site. Using published rate constants (determined without antimycin), with unknown rate constants allowed to vary, the model failed to fit the data. However, when we allowed the rate constant for quinol oxidation to decrease 1000-fold and the rate constant for semiquinone oxidation by b(566) to depend on the b(562) redox state, the model fit the energized and de-energized data well. In such fits, quinol oxidation was much slower than literature values and slowed further when b(566) was reduced, and reduction of b(562) stabilized the semiquinone when b(566) was oxidized. Thus, superoxide production at Q(o) depends on the reduction states of b(566) and b(562) and fits the Q-cycle only if particular rate constants are altered when b oxidation is prevented by antimycin. These mechanisms limit superoxide production and short circuiting of the Q-cycle when electron transfer slows.
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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 [33]
In the citing paper
“Under very specific conditions, complex II can also modulate the superoxide production at the Q o site of complex III [15,16,33] (Fig. 3B).”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [33]
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 [33]
In the citing paper
“In isolated rat heart mitochondria, complex II inhibitors can increase the superoxide production at the Q o site of complex III only under the specific conditions indicated in Section 3.2 and Fig. 3B [15,16,33], i.e. when succinate is the predominant substrate and under conditions of 'oxidant-induced reduction'.”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [33]
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Citations
Cites
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Self-citationComplex iii releases superoxide to both sides of the inner mitochondrial membrane
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- Harman, 1998, J. Int. Fed. Clin. Chem., 10, 24
- Funahashi, 2007, In Silico Biol., 7, S81
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Mitochondrial electron transport chain, ROS generation and uncoupling (Review)
Zhao, R., Jiang, S., Zhang, L., & Yu, Z. (2019) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2019.4188 · Cited by 1,497
Brand, M. D. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.04.001 · Cited by 1,063
Self-citationQuinlan, C. L., Orr, A. L., Perevoshchikova, I. V., Treberg, J. R., Ackrell, B. A., & Brand, M. D. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.374629 · Cited by 670
Self-citationSites of reactive oxygen species generation by mitochondria oxidizing different substrates
Quinlan, C. L., Perevoshchikova, I. V., Hey‐Mogensen, M., Orr, A. L., & Brand, M. D. (2013) · Redox Biology · doi:10.1016/j.redox.2013.04.005 · Cited by 608
Self-citationSuccinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis
Tretter, L., Patócs, A., & Chinopoulos, C. (2016) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2016.03.012 · Cited by 550
Metadata
- Authors
- Quinlan, C. L., Gerencser, A. A., Treberg, J. R., & Brand, M. D.
- Affiliations
- Buck Institute for Research on Aging (US)
- Corresponding author
- Quinlan, Casey L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 286
- Issue
- 36
- Pages
- 31361-31372
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3173136
- OpenAlex
- W2009383015
- Cited by
- 200
- References
- 52
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 11 · 2023: 19 · 2022: 11 · 2021: 21 · 2020: 17 · 2019: 9 · 2018: 11 · 2017: 11 · 2016: 13 · 2015: 10 · 2014: 17 · 2013: 14 · 2012: 9
- FWCI
- 5.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG033542, PL1AG032118, P01AG025901)
- 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, antimycin, mitochondrial complex III, Q-cycle, cytochrome b562, semiquinone, kinetic modeling, electron transfer, membrane potential, mitochondrial respiration, reactive oxygen species
- MeSH terms
- Animals, Anti-Bacterial Agents, Antimycin A, Cytochrome b Group, Electron Transport, Female, Kinetics, Mitochondria, Oxidation-Reduction, Quinones, Superoxides, Electron Transport Complex III, Rats, Wistar, Escherichia coli Proteins, Rats
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