TY - JOUR
T1 - Mitochondrial succinate is instrumental for HIF1α nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions
AU - Brière, Jean Jacques
AU - Favier, Judith
AU - Bénit, Paule
AU - El Ghouzzi, Vincent
AU - Lorenzato, Annalisa
AU - Rabier, Daniel
AU - Di Renzo, Maria Flavia
AU - Gimenez-Roqueplo, Anne Paule
AU - Rustin, Pierre
PY - 2005/11
Y1 - 2005/11
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddi359
DO - 10.1093/hmg/ddi359
M3 - Article
C2 - 16195397
AN - SCOPUS:27744606274
VL - 14
SP - 3263
EP - 3269
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 21
ER -