Mitochondrial redox cycling of mitoquinone leads to superoxide production and cellular apoptosis.
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.
Doughan
Abdulrahman K
AK
Free Radical in Medicine Core, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Dikalov
Sergey I
SI
D000818:Animals; D001011:Aorta / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects*; D002417:Cattle; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D042967:Electron Transport Complex I / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008954:Models, Biological; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014451:Ubiquinone / Q000737:chemistry / Q000494:pharmacology* / Q000031:analogs & derivatives; D024483:Vitamin K 3 / Q000494:pharmacology
D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; D013481:Superoxides; D014451:Ubiquinone; C429014:mitoquinone; D024483:Vitamin K 3; D006861:Hydrogen Peroxide; D042967:Electron Transport Complex I