Mitochondrial Protein Lipoylation and the 2-Oxoglutarate Dehydrogenase Complex Controls HIF1 alpha Stability in Aerobic Conditions

作者：Burr Stephen P; Costa Ana S H; Grice Guinevere L; Timms Richard T; Lobb Ian T; Freisinger Peter; Dodd Roger B; Dougan Gordon; Lehner Paul J; Frezza Christian; Nathan James A^*

来源：Cell Metabolism, 2016, 24(5): 740-752.

DOI：10.1016/j.cmet.2016.09.015

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.

• 出版日期2016-11-8
• 单位河北医科大学