title: Fatty acid labeling from glutamine in hypoxia can be explained by isotope exchange without net reductive isocitrate dehydrogenase (IDH) flux.
abstract: Acetyl-CoA is an important anabolic precursor for lipid biosynthesis. In the conventional view of mammalian metabolism, acetyl-CoA is primarily derived by the oxidation of glucose-derived pyruvate in mitochondria. Recent studies have employed isotope tracers to show that in cancer cells grown in hypoxia or with defective mitochondria, a major fraction of acetyl-CoA is produced via another route, reductive carboxylation of glutamine-derived α-ketoglutarate (catalyzed by reverse flux through isocitrate dehydrogenase, IDH). Here, we employ a quantitative flux model to show that in hypoxia and in cells with defective mitochondria, oxidative IDH flux persists and may exceed the reductive flux. Therefore, IDH flux may not be a net contributor to acetyl-CoA production, although we cannot rule out net reductive IDH flux in some compartments. Instead of producing large amounts of net acetyl-CoA reductively, the cells adapt by reducing their demand for acetyl-CoA by importing rather than synthesizing fatty acids. Thus, fatty acid labeling from glutamine in hypoxia can be explained by spreading of label without net reductive IDH flux.
authors.affiliation: From the Lewis-Sigler Institute for Integrative Genomics and.
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.forename: Jurre J
authors.initials: JJ
authors.lastname: Kamphorst
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.forename: Tomer
authors.initials: T
authors.lastname: Shlomi
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism*; D005973:Glutamine / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism; D010084:Oxidation-Reduction
chemical_list: D005227:Fatty Acids; D007656:Ketoglutaric Acids; D005973:Glutamine; D000105:Acetyl Coenzyme A; D007521:Isocitrate Dehydrogenase
keywords: Cancer; Hypoxia; Isotopic Tracers; Metabolism; Mitochondrial Metabolism
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