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J. Biol. Chem., Vol. 278, Issue 48, 47629-47635, November 28, 2003

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The Ubiquinone-binding Site of the Saccharomyces cerevisiae Succinate-Ubiquinone Oxidoreductase Is a Source of Superoxide^*

Jing Guo and Bernard D. Lemire

From the Canadian Institutes of Health, Membrane Protein Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

The mitochondrial succinate dehydrogenase (SDH) is a tetrameric iron-sulfur flavoprotein of the Krebs cycle and of the respiratory chain. A number of mutations in human SDH genes are responsible for the development of paragangliomas, cancers of the head and neck region. The mev-1 mutation in the Caenorhabditis elegans gene encoding the homolog of the SDHC subunit results in premature aging and hypersensitivity to oxidative stress. It also increases the production of superoxide radicals by the enzyme. In this work, we used the yeast succinate dehydrogenase to investigate the molecular and catalytic effects of paraganglioma- and mev-1-like mutations. We mutated Pro-190 of the yeast Sdh2p subunit to Gln (P190Q) and recreated the C. elegans mev-1 mutation by converting Ser-94 in the Sdh3p subunit into a glutamate residue (S94E). The P190Q and S94E mutants have reduced succinate-ubiquinone oxidoreductase activities and are hypersensitive to oxygen and paraquat. Although the mutant enzymes have lower turnover numbers for ubiquinol reduction, larger fractions of the remaining activities are diverted toward superoxide production. The P190Q and S94E mutations are located near the proximal ubiquinone-binding site, suggesting that the superoxide radicals may originate from a ubisemiquinone intermediate formed at this site during the catalytic cycle. We suggest that certain mutations in SDH can make it a significant source of superoxide production in mitochondria, which may contribute directly to disease progression. Our data also challenge the dogma that superoxide production by SDH is a flavin-mediated event rather than a quinone-mediated one.

Received for publication, June 16, 2003 , and in revised form, September 3, 2003.

^* This work was supported by the Canadian Institutes of Health Research Grant MT-15290. 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.

To whom correspondence should be addressed. Tel.: 780-492-4853; Fax: 780-492-0886; E-mail: bernard.lemire{at}ualberta.ca.

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