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

Molecular Systems Biology

Jing Fan³  Jurre J Kamphorst³  Robin Mathew¹  Michelle K Chung³  Eileen White¹  Tomer Shlomi² 

[1] The Cancer Institute of New Jersey, New Brunswick, NJ, USA;Department of Computer Science, Technion, Haifa, Israel;Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA

关键词: cancer bioenergetics;    isotope tracing;    metabolic flux analysis;   

DOI  :  10.1038/msb.2013.65

来源: Wiley

【 摘 要 】

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.

Synopsis

The impact of oncogene activation and hypoxia on energy metabolism is analyzed by integrating quantitative measurements into a redox-balanced metabolic flux model. Glutamine-driven oxidative phosphorylation is found to be a major ATP source even in oncogene-expressing or hypoxic cells.

• The integration of oxygen uptake measurements and LC-MS-based isotope tracer analyses in a redox-balanced metabolic flux model enabled quantitative determination of energy generation pathways in cultured cells.
• In transformed mammalian cells, even in hypoxia (1% oxygen), oxidative phosphorylation produces the majority of ATP.
• The oncogene Ras simultaneously increases glycolysis and decreases oxidative phosphorylation, thus resulting in no net increase in ATP production.
• Glutamine is the major source of high-energy electrons for oxidative phosphorylation, especially upon Ras activation.

【 授权许可】

CC BY-NC-SA   
Copyright © 2013 EMBO and Macmillan Publishers Limited

Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.