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J. Biol. Chem., Vol. 279, Issue 52, 54479-54486, December 24, 2004

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Mitochondrial Oxidative Phosphorylation Is Defective in the Long-lived Mutant clk-1^*

Ernst-Bernhard Kayser, Margaret M. Sedensky, Phil G. Morgan, and Charles L. Hoppel, Supported by the Veterans Affairs Hospitals Medical Services and by National Institutes of Health Grant PO1 AG15885¶||

From the Departments of Anesthesiology and Genetics, University Hospitals and Case Western Reserve University, Cleveland, Ohio 44106 and the ^¶Departments of Pharmacology and Medicine, Department of Veterans Affairs Medical Center, Case Western Reserve University, Cleveland, Ohio 44106

The long-lived mutant of Caenorhabditis elegans, clk-1, is unable to synthesize ubiquinone, CoQ₉. Instead, the mutant accumulates demethoxyubiquinone₉ and small amounts of rhodoquinone₉ as well as dietary CoQ₈. We found a profound defect in oxidative phosphorylation, a test of integrated mitochondrial function, in clk-1 mitochondria fueled by NADH-linked electron donors, i.e. complex I-dependent substrates. Electron transfer from complex I to complex III, which requires quinones, is severely depressed, whereas the individual complexes are fully active. In contrast, oxidative phosphorylation initiated through complex II, which also requires quinones, is completely normal. Here we show that complexes I and II differ in their ability to use the quinone pool in clk-1. This is the first direct demonstration of a differential interaction of complex I and complex II with the endogenous quinone pool. This study uses the combined power of molecular genetics and biochemistry to highlight the role of quinones in mitochondrial function and aging.

Received for publication, March 19, 2004 , and in revised form, July 19, 2004.

^* 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.

Supported in part by National Institutes of Health Grant GM58881.

^|| To whom correspondence should be addressed: Louis Stokes Veterans Affairs Medical Center, Medical Research Service (151W), 10701 East Blvd., Cleveland, OH 44106. Tel.: 216-791-3800 (ext. 5657); Fax: 216-707-5973; E-mail: charles.hoppel{at}case.edu.

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