Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions.
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 1alpha(HIF1alpha) nuclear translocation. HIF1alpha 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 HIF1alpha nuclear translocation. Conversely, alpha-ketoglutarate (alpha-KG) inhibits this nuclear translocation. Therefore, the pseudo-hypoxia pathway in SDH-deficient cells depends on the HIF1alphaprolyl hydroxylase product/substrate (succinate/alpha-KG) equilibrium. In SDH deficiency, organic acids thus appear instrumental in the HIF1alpha-dependent cascade suggesting a direct link between SDH and tumourigenesis.
Brière
Jean-Jacques
JJ
INSERM U676, Hôpital Robert Debré, Paris, France
Favier
Judith
J
Bénit
Paule
P
El Ghouzzi
Vincent
V
Lorenzato
Annalisa
A
Rabier
Daniel
D
Di Renzo
Maria Flavia
MF
Gimenez-Roqueplo
Anne-Paule
AP
Rustin
Pierre
P
D015153:Blotting, Western; D017931:DNA Primers; D005347:Fibroblasts; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D021381:Protein Transport / Q000502:physiology; D013385:Succinate Dehydrogenase / Q000235:genetics*; D019802:Succinic Acid / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
D017931:DNA Primers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D007656:Ketoglutaric Acids; D013481:Superoxides; D019802:Succinic Acid; D007501:Iron; D013385:Succinate Dehydrogenase