title: Mitochondrial Protein Lipoylation and the 2-Oxoglutarate Dehydrogenase Complex Controls HIF1α Stability in Aerobic Conditions.
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.
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Burr
authors.affiliation: Hutchinson MRC Cancer Unit, University of Cambridge, Cambridge, CB2 0XZ, UK.
authors.forename: Ana S H
authors.initials: AS
authors.lastname: Costa
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
authors.forename: Guinevere L
authors.initials: GL
authors.lastname: Grice
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Timms
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
authors.forename: Ian T
authors.initials: IT
authors.lastname: Lobb
authors.affiliation: Kreiskliniken Reutlingen GmbH, 72764 Stuttgart, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Freisinger
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Dodd
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, CB2 0XY, UK; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lehner
authors.affiliation: Hutchinson MRC Cancer Unit, University of Cambridge, Cambridge, CB2 0XZ, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Frezza
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK. Electronic address: jan33@cam.ac.uk.
authors.forename: James A
authors.initials: JA
authors.lastname: Nathan
mesh_terms: D000332:Aerobiosis; D002460:Cell Line; D005820:Genetic Testing; D018095:Germ-Line Mutation / Q000235:genetics; D005977:Glutarates / Q000378:metabolism; D006367:HeLa Cells; D006720:Homozygote; D006801:Humans; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D054878:Lipoylation; D024101:Mitochondrial Proteins / Q000378:metabolism*; D011392:Proline / Q000378:metabolism; D055550:Protein Stability; D013466:Sulfurtransferases
chemical_list: D005977:Glutarates; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D024101:Mitochondrial Proteins; C019417:alpha-hydroxyglutarate; D011392:Proline; D007655:Ketoglutarate Dehydrogenase Complex; D013466:Sulfurtransferases; C116435:lipoic acid synthase