title: Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells.
abstract: The tricarboxylic acid (TCA) cycle is the central hub of oxidative metabolism, running in the classic forward direction to provide carbon for biosynthesis and reducing agents for generation of ATP. Our metabolic tracer studies in melanoma cells showed that in hypoxic conditions the TCA cycle is largely disconnected from glycolysis. By studying the TCA branch point metabolites, acetyl CoA and citrate, as well as the metabolic endpoint glutamine and fatty acids, we developed a comprehensive picture of the rewiring of the TCA cycle that occurs in hypoxia. Hypoxic tumor cells maintain proliferation by running the TCA cycle in reverse. The source of carbon for acetyl CoA, citrate, and fatty acids switches from glucose in normoxia to glutamine in hypoxia. This hypoxic flux from glutamine into fatty acids is mediated by reductive carboxylation. This reductive carboxylation is catalyzed by two isocitrate dehydrogenases, IDH1 and IDH2. Their combined action is necessary and sufficient to effect the reverse TCA flux and maintain cellular viability.
authors.affiliation: Sanford-Burnham Medical Research Institute, Cancer Research Center, La Jolla, CA, USA. filipp@sanfordburnham.org
authors.forename: Fabian V
authors.initials: FV
authors.lastname: Filipp
authors.forename: David A
authors.initials: DA
authors.lastname: Scott
authors.forename: Ze'ev A
authors.initials: ZA
authors.lastname: Ronai
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Osterman
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Smith
mesh_terms: D045744:Cell Line, Tumor; D002952:Citric Acid Cycle / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008545:Melanoma / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000494:pharmacology; D012878:Skin Neoplasms / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D034741:RNA, Small Interfering; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human