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Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF- prolylhydroxylase

Selak, M.A. and Armour, S.M. and MacKenzie, E.D. and Boulahbel, H. and Watson, D.G. and Mansfield, K.D. and Pan, Y. and Simon, M.C. and Thompson, C.B. and Gottlieb, E. (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF- prolylhydroxylase. Cancer Cell, 7. pp. 77-85. ISSN 1535-6108

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Several mitochondrial proteins are tumor suppressors. These include succinate dehydrogenase (SDH) and fumarate hydratase, both enzymes of the tricarboxylic acid (TCA) cycle. However, to date, the mechanisms by which defects in the TCA cycle contribute to tumor formation have not been elucidated. Here we describe a mitochondrion-to-cytosol signaling pathway that links mitochondrial dysfunction to oncogenic events: succinate, which accumulates as a result of SDH inhibition, inhibits HIF-α prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1α. These results suggest a mechanistic link between SDH mutations and HIF-1α induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations.