title: Hypoxia promotes isocitrate dehydrogenase-dependent 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 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.
authors: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: David R
authors: DR
authors: Wise
authors: Patrick S
authors: PS
authors: Ward
authors: Jessica E S
authors: JE
authors: Shay
authors: Justin R
authors: JR
authors: Cross
authors: Joshua J
authors: JJ
authors: Gruber
authors: Uma M
authors: UM
authors: Sachdeva
authors: Jesse M
authors: JM
authors: Platt
authors: Raymond G
authors: RG
authors: DeMatteo
authors: M Celeste
authors: MC
authors: Simon
authors: Craig B
authors: CB
authors: Thompson
mesh_terms: D002264:Carboxylic Acids / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002951:Citrates / Q000378:metabolism*; D002952:Citric Acid Cycle; D008401:Gas Chromatography-Mass Spectrometry; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D034622:RNA Interference
chemical_list: D002264:Carboxylic Acids; D002951:Citrates; D051793:Hypoxia-Inducible Factor 1; D007656:Ketoglutaric Acids; D005973:Glutamine; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D005947:Glucose