Hypoxia promotes isocitrate dehydrogenasedependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability Journal Article
| Authors: | Wise, D. R.; Ward, P. S.; Shay, J. E. S.; Cross, J. R.; Gruber, J. J.; Sachdeva, U. M.; Platt, J. M.; DeMatteo, R. G.; Simon, M. C.; Thompson, C. B. |
| Article Title: | Hypoxia promotes isocitrate dehydrogenasedependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability |
| Abstract: | 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 glutaminederived α-ketoglutarate even in normoxic conditions. These data support a role for glutamine carboxylation in maintaining citrate synthesis and cell growth under hypoxic conditions. |
| Keywords: | neoplasms; cell proliferation; cell viability; cell survival; cell growth; rna interference; cell line, tumor; enzyme analysis; cancer cell; immunoblotting; citric acid; glucose; cell hypoxia; cell metabolism; oxidation-reduction; glutamine; carboxylic acids; isocitrate dehydrogenase; citric acid cycle; hypoxia inducible factor 1; 2 oxoglutaric acid; hypoxia-inducible factor 1; ketoglutaric acids; gas chromatography-mass spectrometry; aerobic metabolism; citrates; carboxylation; reduced nicotinamide adenine dinucleotide ferrihemoprotein reductase |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 108 |
| Issue: | 49 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2011-12-06 |
| Start Page: | 19611 |
| End Page: | 19616 |
| Language: | English |
| DOI: | 10.1073/pnas.1117773108 |
| PROVIDER: | scopus |
| PMCID: | PMC3241793 |
| PUBMED: | 22106302 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 February 2012" - "CODEN: PNASA" - "Source: Scopus" |
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