| Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. | |
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MedLine Citation:
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PMID: 22106302 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Citrate is a critical metabolite required to support both mitochondrial bioenergetics and cytosolic macromolecular synthesis. When cells proliferate under normoxic conditions, glucose provides the acetyl-CoA that condenses with oxaloacetate to support citrate production. Tricarboxylic acid (TCA) cycle anaplerosis is maintained primarily by glutamine. Here we report that some hypoxic cells are able to maintain cell proliferation despite a profound reduction in glucose-dependent citrate production. In these hypoxic cells, glutamine becomes a major source of citrate. Glutamine-derived α-ketoglutarate is reductively carboxylated by the NADPH-linked mitochondrial isocitrate dehydrogenase (IDH2) to form isocitrate, which can then be isomerized to citrate. The increased IDH2-dependent carboxylation of glutamine-derived α-ketoglutarate in hypoxia is associated with a concomitant increased synthesis of 2-hydroxyglutarate (2HG) in cells with wild-type IDH1 and IDH2. When either starved of glutamine or rendered IDH2-deficient by RNAi, hypoxic cells are unable to proliferate. The reductive carboxylation of glutamine is part of the metabolic reprogramming associated with hypoxia-inducible factor 1 (HIF1), as constitutive activation of HIF1 recapitulates the preferential reductive metabolism of glutamine-derived α-ketoglutarate even in normoxic conditions. These data support a role for glutamine carboxylation in maintaining citrate synthesis and cell growth under hypoxic conditions. |
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Authors:
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David R Wise; Patrick S Ward; Jessica E S Shay; Justin R Cross; Joshua J Gruber; Uma M Sachdeva; Jesse M Platt; Raymond G DeMatteo; M Celeste Simon; Craig B Thompson |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-11-21 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 108 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2011-12-07 Completed Date: 2012-04-13 Revised Date: 2013-02-27 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 19611-6 Citation Subset: IM |
Affiliation:
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Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Carboxylic Acids
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metabolism Cell Hypoxia Cell Line, Tumor Cell Proliferation* Cell Survival Citrates / metabolism* Citric Acid Cycle Gas Chromatography-Mass Spectrometry Glucose / metabolism Glutamine / metabolism Humans Hypoxia-Inducible Factor 1 / genetics, metabolism Immunoblotting Isocitrate Dehydrogenase / genetics, metabolism* Ketoglutaric Acids / metabolism* Neoplasms / genetics, metabolism, pathology Oxidation-Reduction RNA Interference |
| Grant Support | |
ID/Acronym/Agency:
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//Howard Hughes Medical Institute |
| Chemical | |
Reg. No./Substance:
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0/Carboxylic Acids; 0/Citrates; 0/Hypoxia-Inducible Factor 1; 0/Ketoglutaric Acids; 328-50-7/alpha-ketoglutaric acid; 50-99-7/Glucose; 56-85-9/Glutamine; EC 1.1.1.41/Isocitrate Dehydrogenase; EC 1.1.1.41/isocitrate dehydrogenase 2, human; EC 1.1.1.42./IDH1 protein, human |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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