Document Detail

Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability.
MedLine Citation:
PMID:  22106302     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-11-21
Journal Detail:
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:
Created Date:  2011-12-07     Completed Date:  2012-04-13     Revised Date:  2014-07-10    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  19611-6     Citation Subset:  IM    
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MeSH Terms
Carboxylic Acids / metabolism
Cell Hypoxia
Cell Line, Tumor
Cell Proliferation*
Cell Survival
Citrates / metabolism*
Citric Acid Cycle
Gas Chromatography-Mass Spectrometry
Glucose / metabolism
Glutamine / metabolism
Hypoxia-Inducible Factor 1 / genetics,  metabolism
Isocitrate Dehydrogenase / genetics,  metabolism*
Ketoglutaric Acids / metabolism*
Neoplasms / genetics,  metabolism,  pathology
RNA Interference
Grant Support
P01 CA104838/CA/NCI NIH HHS; R01 CA105463/CA/NCI NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
0/Carboxylic Acids; 0/Citrates; 0/Hypoxia-Inducible Factor 1; 0/Ketoglutaric Acids; 0RH81L854J/Glutamine; 328-50-7/alpha-ketoglutaric acid; EC Dehydrogenase; EC dehydrogenase 2, human; EC protein, human; IY9XDZ35W2/Glucose

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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