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

M.A. Selak, S.M. Armour, E.D. MacKenzie, H. Boulahbel, D.G. Watson, K.D. Mansfield, Y. Pan, M.C. Simon, C.B. Thompson, E. Gottlieb

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Abstract

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.
Original languageEnglish
Pages (from-to)77-85
Number of pages9
JournalCancer Cell
Volume7
DOIs
Publication statusPublished - 2005

Keywords

  • tricarboxylic acid (TCA) cycle
  • succinate dehydrogenase (SDH)
  • prolylhydroxylase

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    Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., ... Gottlieb, E. (2005). Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF- prolylhydroxylase. Cancer Cell, 7, 77-85. https://doi.org/10.1016/j.ccr.2004.11.022