Mitochondrial Protein Lipoylation and the 2-Oxoglutarate Dehydrogenase Complex Controls HIF1α Stability in Aerobic Conditions

被引：140

作者：

Burr, Stephen P. ^{[1
]}

Costa, Ana S. H. ^{[2
]}

Grice, Guinevere L. ^{[1
]}

Timms, Richard T. ^{[1
]}

Lobb, Ian T. ^{[1
]}

Freisinger, Peter ^{[3
]}

Dodd, Roger B. ^{[1
]}

Dougan, Gordon ^{[4
,5
]}

Lehner, Paul J. ^{[1
]}

Frezza, Christian ^{[2
]}

Nathan, James A. ^{[1
]}

机构：

[1] Univ Cambridge, Dept Med, Cambridge Inst Med Res, Cambridge CB2 0XY, England

[2] Univ Cambridge, Hutchinson MRC Canc Unit, Cambridge CB2 0XZ, England

[3] Kreiskliniken Reutlingen GmbH, D-72764 Stuttgart, Germany

[4] Univ Cambridge, Dept Med, Cambridge CB2 0XY, England

[5] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England

来源：

Cell Metabolism | 2016年 / 24卷 / 05期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

ONCOMETABOLITE; 2-HYDROXYGLUTARATE; PROLYL HYDROXYLASE; HUMAN-CELLS; HYPOXIA; ACTIVATION; OXYGEN; HIF; DIOXYGENASES; DEFICIENCY; METABOLISM;

D O I：

10.1016/j.cmet.2016.09.015

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Hypoxia-inducible transcription factors (HIFs) control adaptation to low oxygen environments by activating genes involved in metabolism, angiogenesis, and redox homeostasis. The finding that HIFs are also regulated by small molecule metabolites highlights the need to understand the complexity of their cellular regulation. Here we use a forward genetic screen in near-haploid human cells to identify genes that stabilize HIFs under aerobic conditions. We identify two mitochondrial genes, oxoglutarate dehydrogenase (OGDH) and lipoic acid synthase (LIAS), which when mutated stabilize HIF1 alpha in a non-hydroxylated form. Disruption of OGDH complex activity in OGDH or LIAS mutants promotes L-2-hydroxyglutarate formation, which inhibits the activity of the HIF alpha prolyl hydroxylases (PHDs) and TET 2-oxoglutarate dependent dioxygenases. We also find that PHD activity is decreased in patients with homozygous germline mutations in lipoic acid synthesis, leading to HIF1 activation. Thus, mutations affecting OGDHC activity may have broad implications for epigenetic regulation and tumorigenesis.

引用

页码：740 / 752

页数：13

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