期刊
Cell Metabolism
卷 24, 期 5, 页码 740-752出版社
CELL PRESS
DOI: 10.1016/j.cmet.2016.09.015
关键词
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资金
- Wellcome Trust [102770/Z/13/Z, 084957/Z/08/Z, 100140]
- Medical Research Council
- Medical Research Council [MC_UU_12022/6] Funding Source: researchfish
- MRC [MC_UU_12022/6] Funding Source: UKRI
- Wellcome Trust [084957/Z/08/Z, 102770/Z/13/Z] Funding Source: Wellcome Trust
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.
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