Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions.
Hum Mol Genet
; 14(21): 3263-9, 2005 Nov 01.
Article
em En
| MEDLINE
| ID: mdl-16195397
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 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.
Buscar no Google
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Succinato Desidrogenase
/
Ácido Succínico
/
Subunidade alfa do Fator 1 Induzível por Hipóxia
/
Mitocôndrias
Limite:
Humans
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article