Interactions of mitochondria-targeted and untargeted ubiquinones with the mitochondrial respiratory chain and reactive oxygen species. Implications for the use of exogenous ubiquinones as therapies and experimental tools.

TitleInteractions of mitochondria-targeted and untargeted ubiquinones with the mitochondrial respiratory chain and reactive oxygen species. Implications for the use of exogenous ubiquinones as therapies and experimental tools.
Publication TypeJournal Article
Year of Publication2005
AuthorsJames, AM, Cochemé, HM, Smith, RAJ, Murphy, MP
JournalJ Biol Chem
Volume280
Issue22
Pagination21295-312
Date Published2005 Jun 03
ISSN0021-9258
KeywordsAconitate Hydratase, Animals, Antioxidants, Binding Sites, Cattle, Dose-Response Relationship, Drug, Electron Transport, Fatty Acids, Glycerolphosphate Dehydrogenase, Hydrogen Peroxide, Lipid Peroxidation, Magnetic Resonance Spectroscopy, Mitochondria, Mitochondria, Liver, Models, Biological, Models, Chemical, Models, Molecular, Myocardium, Nitric Oxide, Oxidation-Reduction, Oxidative Stress, Oxygen, Oxygen Consumption, Phosphorylation, Protein Binding, Rats, Reactive Oxygen Species, Saccharomyces cerevisiae, Signal Transduction, Sulfhydryl Compounds, Superoxides, Time Factors, Ubiquinone
Abstract

Antioxidants, such as ubiquinones, are widely used in mitochondrial studies as both potential therapies and useful research tools. However, the effects of exogenous ubiquinones can be difficult to interpret because they can also be pro-oxidants or electron carriers that facilitate respiration. Recently we developed a mitochondria-targeted ubiquinone (MitoQ10) that accumulates within mitochondria. MitoQ10 has been used to prevent mitochondrial oxidative damage and to infer the involvement of mitochondrial reactive oxygen species in signaling pathways. However, uncertainties remain about the mitochondrial reduction of MitoQ10, its oxidation by the respiratory chain, and its pro-oxidant potential. Therefore, we compared MitoQ analogs of varying alkyl chain lengths (MitoQn, n = 3-15) with untargeted exogenous ubiquinones. We found that MitoQ10 could not restore respiration in ubiquinone-deficient mitochondria because oxidation of MitoQ analogs by complex III was minimal. Complex II and glycerol 3-phosphate dehydrogenase reduced MitoQ analogs, and the rate depended on chain length. Because of its rapid reduction and negligible oxidation, MitoQ10 is a more effective antioxidant against lipid peroxidation, peroxynitrite and superoxide. Paradoxically, exogenous ubiquinols also autoxidize to generate superoxide, but this requires their deprotonation in the aqueous phase. Consequently, in the presence of phospholipid bilayers, the rate of autoxidation is proportional to ubiquinol hydrophilicity. Superoxide production by MitoQ10 was insufficient to damage aconitase but did lead to hydrogen peroxide production and nitric oxide consumption, both of which may affect cell signaling pathways. Our results comprehensively describe the interaction of exogenous ubiquinones with mitochondria and have implications for their rational design and use as therapies and as research tools to probe mitochondrial function.

DOI10.1074/jbc.M501527200
Alternate JournalJ. Biol. Chem.
Citation Key10.1074/jbc.M501527200
PubMed ID15788391