title: Reductive carboxylation supports growth in tumour cells with defective mitochondria.
abstract: Mitochondrial metabolism provides precursors to build macromolecules in growing cancer cells. In normally functioning tumour cell mitochondria, oxidative metabolism of glucose- and glutamine-derived carbon produces citrate and acetyl-coenzyme A for lipid synthesis, which is required for tumorigenesis. Yet some tumours harbour mutations in the citric acid cycle (CAC) or electron transport chain (ETC) that disable normal oxidative mitochondrial function, and it is unknown how cells from such tumours generate precursors for macromolecular synthesis. Here we show that tumour cells with defective mitochondria use glutamine-dependent reductive carboxylation rather than oxidative metabolism as the major pathway of citrate formation. This pathway uses mitochondrial and cytosolic isoforms of NADP(+)/NADPH-dependent isocitrate dehydrogenase, and subsequent metabolism of glutamine-derived citrate provides both the acetyl-coenzyme A for lipid synthesis and the four-carbon intermediates needed to produce the remaining CAC metabolites and related macromolecular precursors. This reductive, glutamine-dependent pathway is the dominant mode of metabolism in rapidly growing malignant cells containing mutations in complex I or complex III of the ETC, in patient-derived renal carcinoma cells with mutations in fumarate hydratase, and in cells with normal mitochondria subjected to acute pharmacological ETC inhibition. Our findings reveal the novel induction of a versatile glutamine-dependent pathway that reverses many of the reactions of the canonical CAC, supports tumour cell growth, and explains how cells generate pools of CAC intermediates in the face of impaired mitochondrial metabolism.
authors.affiliation: Department of Pediatrics, University of Texas - Southwestern Medical Center at Dallas, Dallas, Texas 75390-9063, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Mullen
authors.forename: William W
authors.initials: WW
authors.lastname: Wheaton
authors.forename: Eunsook S
authors.initials: ES
authors.lastname: Jin
authors.forename: Pei-Hsuan
authors.initials: PH
authors.lastname: Chen
authors.forename: Lucas B
authors.initials: LB
authors.lastname: Sullivan
authors.forename: Tzuling
authors.initials: T
authors.lastname: Cheng
authors.forename: Youfeng
authors.initials: Y
authors.lastname: Yang
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D019343:Citric Acid / Q000378:metabolism; D004579:Electron Transport; D042967:Electron Transport Complex I / Q000378:metabolism; D014450:Electron Transport Complex III / Q000378:metabolism; D005649:Fumarate Hydratase / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D009249:NADP / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*
chemical_list: D005973:Glutamine; D019343:Citric Acid; D009249:NADP; D000105:Acetyl Coenzyme A; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D005649:Fumarate Hydratase; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; D005947:Glucose
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