Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia

Fan, J., Kamphorst, J.J. , Mathew, R., Chung, M.K., White, E., Shlomi, T. and Rabinowitz, J.D. (2013) Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia. Molecular Systems Biology, 9, 712. (doi: 10.1038/msb.2013.65) (PMID:24301801) (PMCID:PMC3882799)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Kamphorst, Dr Jurre
• Authors: Fan, J., Kamphorst, J.J., Mathew, R., Chung, M.K., White, E., Shlomi, T., and Rabinowitz, J.D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Molecular Systems Biology
• Publisher: EMBO Press
• ISSN: 1744-4292
• ISSN (Online): 1744-4292
• Copyright Holders: Copyright © 2013 EMBO and Macmillan Publishers Limited
• First Published: First published in Molecular Systems Biology 9:712
• Publisher Policy: Reproduced under a Creative Commons License