title: Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia.
abstract: Mammalian cells can generate ATP via glycolysis or mitochondrial respiration. Oncogene activation and hypoxia promote glycolysis and lactate secretion. The significance of these metabolic changes to ATP production remains however ill defined. Here, we integrate LC-MS-based isotope tracer studies with oxygen uptake measurements in a quantitative redox-balanced metabolic flux model of mammalian cellular metabolism. We then apply this approach to assess the impact of Ras and Akt activation and hypoxia on energy metabolism. Both oncogene activation and hypoxia induce roughly a twofold increase in glycolytic flux. Ras activation and hypoxia also strongly decrease glucose oxidation. Oxidative phosphorylation, powered substantially by glutamine-driven TCA turning, however, persists and accounts for the majority of ATP production. Consistent with this, in all cases, pharmacological inhibition of oxidative phosphorylation markedly reduces energy charge, and glutamine but not glucose removal markedly lowers oxygen uptake. Thus, glutamine-driven oxidative phosphorylation is a major means of ATP production even in hypoxic cancer cells.
authors.affiliation: Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.forename: Jurre J
authors.initials: JJ
authors.lastname: Kamphorst
authors.forename: Robin
authors.initials: R
authors.lastname: Mathew
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Chung
authors.forename: Eileen
authors.initials: E
authors.lastname: White
authors.forename: Tomer
authors.initials: T
authors.lastname: Shlomi
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D053858:Metabolic Networks and Pathways; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism; D010085:Oxidative Phosphorylation; D049490:Systems Biology
chemical_list: D005973:Glutamine; D000255:Adenosine Triphosphate