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J. Biol. Chem., Vol. 282, Issue 20, 14708-14718, May 18, 2007

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Interaction of the Mitochondria-targeted Antioxidant MitoQ with Phospholipid Bilayers and Ubiquinone Oxidoreductases^*

Andrew M. James, Mark S. Sharpley, Abdul-Rahman B. Manas, Frank E. Frerman^¶, Judy Hirst, Robin A. J. Smith, and Michael P. Murphy¹

From the Medical Research Council Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, United Kingdom, the ^¶Departments of Pediatrics and Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado 80262, and the Department of Chemistry, University of Otago, P. O. Box 56, Dunedin 9001, New Zealand

MitoQ₁₀ is a ubiquinone that accumulates within mitochondria driven by a conjugated lipophilic triphenylphosphonium cation (TPP⁺). Once there, MitoQ₁₀ is reduced to its active ubiquinol form, which has been used to prevent mitochondrial oxidative damage and to infer the involvement of reactive oxygen species in signaling pathways. Here we show MitoQ₁₀ is effectively reduced by complex II, but is a poor substrate for complex I, complex III, and electron-transferring flavoprotein (ETF):quinone oxidoreductase (ETF-QOR). This differential reactivity could be explained if the bulky TPP⁺ moiety sterically hindered access of the ubiquinone group to enzyme active sites with a long, narrow access channel. Using a combination of molecular modeling and an uncharged analog of MitoQ₁₀ with similar sterics (tritylQ₁₀), we infer that the interaction of MitoQ₁₀ with complex I and ETF-QOR, but not complex III, is inhibited by its bulky TPP⁺ moiety. To explain its lack of reactivity with complex III we show that the TPP⁺ moiety of MitoQ₁₀ is ineffective at quenching pyrene fluorophors deeply buried within phospholipid bilayers and thus is positioned near the membrane surface. This superficial position of the TPP⁺ moiety, as well as the low solubility of MitoQ₁₀ in non-polar organic solvents, suggests that the concentration of the entire MitoQ₁₀ molecule in the membrane core is very limited. As overlaying MitoQ₁₀ onto the structure of complex III indicates that MitoQ₁₀ cannot react with complex III without its TPP⁺ moiety entering the low dielectric of the membrane core, we conclude that the TPP⁺ moiety does anchor the tethered ubiquinol group out of reach of the active site(s) of complex III, thus explaining its slow oxidation. In contrast the ubiquinone moiety of MitoQ₁₀ is able to quench fluorophors deep within the membrane core, indicating a high concentration of the ubiquinone moiety within the membrane and explaining its good anti-oxidant efficacy. These findings will facilitate the rational design of future mitochondria-targeted molecules.

Received for publication, December 14, 2006 , and in revised form, February 27, 2007.

^* This work was supported in part by the Medical Research Council, the 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence should be addressed: Medical Research Council Dunn Human Nutrition Unit, Wellcome Trust/MRC Bldg., Hills Road, Cambridge CB2 2XY, UK. Tel.: 44-1223-252900; Fax: 44-1223-252905; E-mail: mpm{at}mrc-dunn.cam.ac.uk.

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