Mitochondrial Redox Cycling of Mitoquinone Leads to Superoxide Production and Cellular Apoptosis
Abstract
The mitochondria-targeted drug mitoquinone (MitoQ) has been used as an antioxidant that may selectively block mitochondrial oxidative damage; however, it has been recently suggested to increase reactive oxygen species (ROS) generation in malate- and glutamate-fueled mitochondria. To address this controversy, we studied the effects of MitoQ on endothelial and mitochondrial ROS production. We found that in a cell-free system with flavin-containing enzyme cytochrome P-450 reductase, MitoQ is a very efficient redox cycling agent and produced more superoxide compared with equal concentrations of menadione (10-1,000 nM). Treatment of endothelial cells with MitoQ resulted in a dramatic increase in superoxide production. In isolated mitochondria, MitoQ increased complex I-driven mitochondrial ROS production, whereas supplementation with ubiquinone-10 had no effect on ROS production. Similar results were observed in mitochondria isolated from endothelial cells incubated for 1 h with MitoQ. Inhibitor analysis suggested that the redox cycling of MitoQ occurred at two sites on complex I, proximal and distal to the rotenone-binding site. This was confirmed by demonstrating the redox cycling of MitoQ on purified mitochondrial complex I as well as NADH-fueled submitochondrial particles. Mitoquinone time- and dose-dependently increased endothelial cell apoptosis. These findings demonstrate that MitoQ may be prooxidant and proapoptotic because its quinone group can participate in redox cycling and superoxide production. In light of these results, studies using mitoquinone as an antioxidant should be interpreted with caution.
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In bovine aortic endothelial cell isolated mitochondria, MitoQ induces superoxide, apoptosis, and redox cycling at complex I in a concentration and time dependent manner.
“In bovine aortic endothelial cell isolated mitochondria, MitoQ was shown to induce superoxide, apoptosis, and redox cycling at complex I in a concentration and time dependent manner [32].”
From Mitochondrially targeted compounds and their impact on cellular bioenergetics (2013) · cites this paper as [32]
During respiration on complex I substrates, superoxide appears to result from redox cycling of endogenous CoQ10 or exogenous analogues at Q-binding sites within complex I.
“During respiration on complex I substrates, superoxide appears to result from redox cycling of endogenous CoQ10 or exogenous analogues at Q-binding sites within complex I (84, 185, 241).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [84]
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- Authors
- Doughan, A. K., & Dikalov, S. I.
- Affiliations
- Emory University (US)
- ORCID
- Dikalov, Sergey I.
- Venue
- Antioxidants & Redox Signaling
- Publisher
- SAGE Publications
- Published
- 2007-11
- Volume
- 9
- Issue
- 11
- Pages
- 1825-1836
- ISSN
- 1523-0864 (ISSN-L)
- 1557-7716
- OpenAlex
- W1996885665
- Cited by
- 172
- References
- 31
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 6 · 2023: 7 · 2022: 6 · 2021: 13 · 2020: 10 · 2019: 7 · 2018: 11 · 2017: 13 · 2016: 8 · 2015: 7 · 2014: 11 · 2013: 7 · 2012: 13
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Antioxidants and Redox Signaling (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01hl075209-05)
- National Heart, Lung, and Blood Institute (P0-1 HL-075209, P01HL058000)
- 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 › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- mitoquinone, redox cycling, superoxide production, mitochondrial reactive oxygen species, mitochondrial complex I, endothelial cell apoptosis, pro-oxidant activity, NADPH-cytochrome P450 reductase, ubiquinone-10, menadione
- MeSH terms
- Animals, Aorta, Cattle, Cells, Cultured, Chromatography, High Pressure Liquid, Dose-Response Relationship, Drug, Electron Spin Resonance Spectroscopy, Endothelium, Vascular, Hydrogen Peroxide, Kinetics, Mitochondria, Models, Biological, Organophosphorus Compounds, Oxidation-Reduction, Subcellular Fractions, Superoxides, Ubiquinone, Molecular Structure, Apoptosis, Reactive Oxygen Species, Vitamin K 3, Endothelial Cells, Electron Transport Complex I
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