The mitochondrial succinate dehydrogenase (SDH) is an essential component of the electron transport chain and of the tricar notboxylic 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 paragangli notoma and pheochromocy nottoma. 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 Arg-47 of the Sdh3p subunit to Cys, Glu and Lys and Asp-88 of the Sdh4p subunit to Asn, Glu and Lys. Both Arg-47 and Asp-88 are conserved residues and Arg-47 is a known site of cancer causing mutations in humans. All mutants examined have reduced ubiquinone reductase activities. The SDH3 R47K, SDH4 D88E and 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 (HIF)-1a. 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.
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