Mitochondrial succinate is instrumental for HIF1α nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions
Mitochondrial succinate is instrumental for HIF1α nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions
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DOI：
10.1093/hmg/ddi359
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发表时间：
2005-11-01
影响因子：
3.5
通讯作者：
Rustin, P
中科院分区：
文献类型：
--
作者：
Brière, JJ;Favier, J;Rustin, P
编码琥珀酸脱氢酶（SDH）亚单位B、C和D的基因在神经内分泌组织中起肿瘤抑制剂的作用。肿瘤形成与琥珀酸积累有关。在副神经节瘤细胞中，发现两种形式的SDHA（I型，II型），这可能会排除显着的琥珀酸积累的情况下，在任何形式的突变。在成纤维细胞中只发现SDHA I型，在这些细胞中，SDHA I型突变导致SDH缺陷、琥珀酸积累和缺氧诱导因子1 α（HIF 1 α）核转位。HIF 1 α核转位没有观察到ATP酶缺陷的成纤维细胞增加超氧化物的产生，并被发现是独立的SDHA突变细胞的细胞铁的可用性。这表明超氧化物和铁都不是HIF 1 α核转位的原因。相反，α-酮戊二酸（α-KG）抑制这种核转位。因此，SDH缺陷细胞中的假缺氧途径取决于HIF 1 α脯氨酰羟化酶产物/底物（琥珀酸/α-KG）平衡。因此，在SDH缺乏症中，有机酸在HIF 1 α依赖性级联反应中起作用，表明SDH与肿瘤发生之间存在直接联系。
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 1 alpha(HIF1 alpha) nuclear translocation. HIF1 alpha 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 HIF1 alpha nuclear translocation. Conversely, alpha-ketoglutarate (alpha-KG) inhibits this nuclear translocation. Therefore, the pseudo-hypoxia pathway in SDH-deficient cells depends on the HIF1 alpha prolyl hydroxylase product/substrate (succinate/alpha-KG) equilibrium. In SDH deficiency, organic acids thus appear instrumental in the HIF1 alpha-dependent cascade suggesting a direct link between SDH and tumourigenesis.