| Mitochondrial redox cycling of mitoquinone leads to superoxide production and cellular apoptosis. | |
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MedLine Citation:
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PMID: 17854275 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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Abdulrahman K Doughan; Sergey I Dikalov |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Antioxidants & redox signaling Volume: 9 ISSN: 1523-0864 ISO Abbreviation: Antioxid. Redox Signal. Publication Date: 2007 Nov |
Date Detail:
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Created Date: 2007-10-22 Completed Date: 2007-12-07 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100888899 Medline TA: Antioxid Redox Signal Country: United States |
Other Details:
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Languages: eng Pagination: 1825-36 Citation Subset: IM |
Affiliation:
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Free Radical in Medicine Core, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Aorta / cytology Apoptosis / drug effects* Cattle Cells, Cultured Chromatography, High Pressure Liquid Dose-Response Relationship, Drug Electron Spin Resonance Spectroscopy Electron Transport Complex I / metabolism Endothelial Cells / drug effects*, metabolism Endothelium, Vascular / cytology Hydrogen Peroxide / metabolism Kinetics Mitochondria / drug effects*, metabolism Models, Biological Molecular Structure Organophosphorus Compounds / chemistry, pharmacology* Oxidation-Reduction Reactive Oxygen Species / metabolism Subcellular Fractions / drug effects, metabolism Superoxides / metabolism* Ubiquinone / chemistry, pharmacology* Vitamin K 3 / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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P0-1 HL075209/HL/NHLBI NIH HHS; P01 HL058000/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Organophosphorus Compounds; 0/Reactive Oxygen Species; 0/mitoquinone; 11062-77-4/Superoxides; 1339-63-5/Ubiquinone; 58-27-5/Vitamin K 3; 7722-84-1/Hydrogen Peroxide; EC 1.6.5.3/Electron Transport Complex I |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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