Document Detail

Mitochondrial redox cycling of mitoquinone leads to superoxide production and cellular apoptosis.
MedLine Citation:
PMID:  17854275     Owner:  NLM     Status:  MEDLINE    
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.
Abdulrahman K Doughan; Sergey I Dikalov
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  9     ISSN:  1523-0864     ISO Abbreviation:  Antioxid. Redox Signal.     Publication Date:  2007 Nov 
Date Detail:
Created Date:  2007-10-22     Completed Date:  2007-12-07     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1825-36     Citation Subset:  IM    
Free Radical in Medicine Core, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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MeSH Terms
Aorta / cytology
Apoptosis / drug effects*
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
Mitochondria / drug effects*,  metabolism
Models, Biological
Molecular Structure
Organophosphorus Compounds / chemistry,  pharmacology*
Reactive Oxygen Species / metabolism
Subcellular Fractions / drug effects,  metabolism
Superoxides / metabolism*
Ubiquinone / chemistry,  pharmacology*
Vitamin K 3 / pharmacology
Grant Support
Reg. No./Substance:
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 Transport Complex I

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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