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J. Biol. Chem., Vol. 280, Issue 22, 21295-21312, June 3, 2005

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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^*

Andrew M. James, Helena M. Cochemé, Robin A. J. Smith¶, and Michael P. Murphy||

From the Medical Research Council Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, United Kingdom and the ^¶Department of Chemistry, University of Otago, P. O. Box 56, Dunedin, New Zealand

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 (MitoQ_n, 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.

Received for publication, February 9, 2005

^* This work was supported by the Medical Research Council, Foundation for Research, Science and Technology New Zealand and by Antipodean Biotechnology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

Recipient of a Ph.D. Studentship from Research into Ageing, United Kingdom.

^|| To whom correspondence should be addressed. Tel.: 44-1223-252900; Fax: 44-1223-252905; E-mail: mpm{at}mrc-dunn.cam.ac.uk.

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