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, Pierre Rustin

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)3263-3269
Number of pages7
JournalHuman Molecular Genetics
Volume14
Issue number21
DOIs
Publication statusPublished - Nov 2005

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Hypoxia-Inducible Factor 1
Succinate Dehydrogenase
Succinic Acid
Fibroblasts
Superoxides
Iron
Paraganglioma
Mutation
Mixed Function Oxygenases
Adenosine Triphosphatases
Neoplasms
Acids
Genes

ASJC Scopus subject areas

  • Genetics

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Mitochondrial succinate is instrumental for HIF1α nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions. / Brière, Jean Jacques; Favier, Judith; Bénit, Paule; El Ghouzzi, Vincent; Lorenzato, Annalisa; Rabier, Daniel; Di Renzo, Maria Flavia; Gimenez-Roqueplo, Anne Paule; Rustin, Pierre.

In: Human Molecular Genetics, Vol. 14, No. 21, 11.2005, p. 3263-3269.

Research output: Contribution to journalArticle

Brière, Jean Jacques ; Favier, Judith ; Bénit, Paule ; El Ghouzzi, Vincent ; Lorenzato, Annalisa ; Rabier, Daniel ; Di Renzo, Maria Flavia ; Gimenez-Roqueplo, Anne Paule ; Rustin, Pierre. / Mitochondrial succinate is instrumental for HIF1α nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions. In: Human Molecular Genetics. 2005 ; Vol. 14, No. 21. pp. 3263-3269.
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