Format

Send to

Choose Destination
Cell Metab. 2016 Nov 8;24(5):740-752. doi: 10.1016/j.cmet.2016.09.015. Epub 2016 Oct 27.

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

Author information

1
Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
2
Hutchinson MRC Cancer Unit, University of Cambridge, Cambridge, CB2 0XZ, UK.
3
Kreiskliniken Reutlingen GmbH, 72764 Stuttgart, Germany.
4
Department of Medicine, University of Cambridge, Cambridge, CB2 0XY, UK; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK.
5
Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK. Electronic address: jan33@cam.ac.uk.

Abstract

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 HIF1α 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 HIFα 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.

PMID:
27923773
PMCID:
PMC5106373
DOI:
10.1016/j.cmet.2016.09.015
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center