Mitochondrial Protein Lipoylation and the 2-Oxoglutarate Dehydrogenase Complex Controls HIF1α Stability in Aerobic Conditions
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
Cell metabolism - 24(2016), 5 vom: 08. Nov., Seite 740-752 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Burr, Stephen P [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 26.06.2017 Date Revised 13.11.2018 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.cmet.2016.09.015 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM266873294 |
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| 520 | |a Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Glutarates |2 NLM | |
| 650 | 7 | |a Hypoxia-Inducible Factor 1, alpha Subunit |2 NLM | |
| 650 | 7 | |a Mitochondrial Proteins |2 NLM | |
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| 700 | 1 | |a Costa, Ana S H |e verfasserin |4 aut | |
| 700 | 1 | |a Grice, Guinevere L |e verfasserin |4 aut | |
| 700 | 1 | |a Timms, Richard T |e verfasserin |4 aut | |
| 700 | 1 | |a Lobb, Ian T |e verfasserin |4 aut | |
| 700 | 1 | |a Freisinger, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Dodd, Roger B |e verfasserin |4 aut | |
| 700 | 1 | |a Dougan, Gordon |e verfasserin |4 aut | |
| 700 | 1 | |a Lehner, Paul J |e verfasserin |4 aut | |
| 700 | 1 | |a Frezza, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Nathan, James A |e verfasserin |4 aut | |
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