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J. Biol. Chem., Vol. 282, Issue 37, 27518-27526, September 14, 2007

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Ubiquinone-binding Site Mutations in the Saccharomyces cerevisiae Succinate Dehydrogenase Generate Superoxide and Lead to the Accumulation of Succinate^*

From the Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

The mitochondrial succinate dehydrogenase (SDH) is an essential component of the electron transport chain and of the tricarboxylic acid cycle. Also known as complex II, this tetrameric enzyme catalyzes the oxidation of succinate to fumarate and reduces ubiquinone. Mutations in the human SDHB, SDHC, and SDHD genes are tumorigenic, leading to the development of several types of tumors, including paraganglioma and pheochromocytoma. The mechanisms linking SDH mutations to oncogenesis are still unclear. In this work, we used the yeast SDH to investigate the molecular and catalytic effects of tumorigenic or related mutations. We mutated Arg⁴⁷ of the Sdh3p subunit to Cys, Glu, and Lys and Asp⁸⁸ of the Sdh4p subunit to Asn, Glu, and Lys. Both Arg⁴⁷ and Asp⁸⁸ are conserved residues, and Arg⁴⁷ is a known site of cancer causing mutations in humans. All of the mutants examined have reduced ubiquinone reductase activities. The SDH3 R47K, SDH4 D88E, and SDH4 D88N mutants are sensitive to hyperoxia and paraquat and have elevated rates of superoxide production in vitro and in vivo.We also observed the accumulation and secretion of succinate. Succinate can inhibit prolyl hydroxylase enzymes, which initiate a proliferative response through the activation of hypoxia-inducible factor 1. We suggest that SDH mutations can promote tumor formation by contributing to both reactive oxygen species production and to a proliferative response normally induced by hypoxia via the accumulation of succinate.

Received for publication, January 22, 2007 , and in revised form, July 18, 2007.

^* This work was supported by Canadian Institute of Health Research Grants MOP-37769 (to B. D. S.) and MT-15290 (to B. D. L.). 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.

¹ Supported by an Alberta Heritage Foundation for Medical Research Graduate Studentship and a Natural Sciences and Engineering Research Council Postgraduate Scholarship.

² Recipient of a Canada Research Chair in Structural Biology.

³ 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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