Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase

We describe a mitochondrion-to-cytosol signaling pathway that links mitochondrial dysfunction to oncogenic events: succinate, which accumulates as a result of succinate dehydrogenase inhibition, inhibits HIF-␣ prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1

Mary A. Selak; Sean M. Armour; Elaine D. MacKenzie; Houda Boulahbel; David G. Watson; Kyle D. Mansfield; Yi Pan; M.Celeste Simon; Craig B. Thompson; Eyal Gottlieb

2005

Scholarcy highlights

  • Inherited or somatic mutations in subunits B, C, or D of the succinate dehydrogenase genes are associated with the development of pheochromocytoma and paraganglioma
  • Inhibition of SDH in cells using small interference RNA leads to HIF-1␣ accumulation and the induction of HIF transcription activity To study the mechanism that links SDH inhibition to HIF-1␣ induction, the RNA interference technique was used to transiently target SDH in cells
  • Endogenous SDHD mRNA levels were analyzed by RT-PCR and found to be lower in cells transfected with either of the two SDHD siRNA constructs as compared to scrambled siRNA control-transfected cells, demonstrating the effectiveness of Di3 and Di4
  • Since elevated levels of HIF-1␣ protein are observed in tumors harboring SDH mutations, the effect of SDH inhibition on HIF-1␣ protein levels was analyzed by Western blot
  • We describe a direct signaling pathway that links mitochondrial dysfunction to tumorigenesis, providing a mechanistic link between mutations in SDH and the highly vascularized tumors which develop as a consequence of HIF-1␣ induction in the absence of VHL mutations
  • We found that hydrogen peroxide can induce HIF-1␣ levels as was previously described, we observed neither reactive oxygen species generation nor a shift to a Succinate accumulated in the mitochondria due to SDH inhibition is transported to the cytosol
  • These results suggest a mechanistic link between succinate dehydrogenase mutations and HIF-1␣ induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations

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