Journal Article

Mitochondrial succinate is instrumental for HIF1α nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions

Jean-Jacques Brière, Judith Favier, Paule Bénit, Vincent El Ghouzzi, Annalisa Lorenzato, Daniel Rabier, Maria Flavia Di Renzo, Anne-Paule Gimenez-Roqueplo and Pierre Rustin

in Human Molecular Genetics

Volume 14, issue 21, pages 3263-3269
Published in print November 2005 | ISSN: 0964-6906
Published online September 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi359
Mitochondrial succinate is instrumental for HIF1α nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions

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The genes encoding succinate dehydrogenase (SDH) subunits B, C and D, act as tumour suppressors in neuro-endocrine tissues. Tumour formation has been associated with succinate accumulation. In paraganglioma cells, two forms of SDHA (type I, II) were found which might preclude significant succinate accumulation in the case of a mutation in either form. In fibroblasts only SDHA type I is found. In these cells, SDHA type I mutation leads to SDH deficiency, succinate accumulation and hypoxia-inducible factor 1α(HIF1α) nuclear translocation. HIF1α nuclear translocation was not observed in ATPase-deficient fibroblasts with increased superoxide production and was found to be independent of cellular iron availability in SDHA-mutant cells. This suggests that neither superoxides nor iron were causative of HIF1α nuclear translocation. Conversely, α-ketoglutarate (α-KG) inhibits this nuclear translocation. Therefore, the pseudo-hypoxia pathway in SDH-deficient cells depends on the HIF1αprolyl hydroxylase product/substrate (succinate/α-KG) equilibrium. In SDH deficiency, organic acids thus appear instrumental in the HIF1α-dependent cascade suggesting a direct link between SDH and tumourigenesis.

Journal Article.  4091 words.  Illustrated.

Subjects: Genetics and Genomics

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