Glutamine‐driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia
Open accessAbstract
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.
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After activation of K-Ras and Akt in transformed cells, 60% of total FADH2 and NADH2 are synthesized from glutamine, while only 30% is derived from glucose.
“Moreover, after the activation of K-Ras and Akt in transformed cells, 60% of the total FADH2 and NADH2 are synthesized from glutamine, while only 30% is derived from glucose140.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [140]
Elevated glutamine anaplerosis and oxidation are likely a consequence of decreased citrate synthase and oxidative IDH flux downstream of PDH while the ETC remained active.
“Elevated glutamine anaplerosis and oxidation are likely a consequence of decreased citrate synthase and oxidative IDH flux downstream of PDH while the ETC remained active (Fan et al., 2013; Le et al., 2012).”
From Regulation of Substrate Utilization by the Mitochondrial Pyruvate Carrier (2014) · cites this paper as Fan et al., 2013
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- Authors
- Fan, J., Kamphorst, J. J., Mathew, R., Chung, M. K., White, E., Shlomi, T., & Rabinowitz, J. D.
- Affiliations
- Princeton University (US)
- Rutgers Cancer Institute (US)
- Rutgers, The State University of New Jersey (US)
- Technion – Israel Institute of Technology (IL)
- Corresponding author
- Rabinowitz, Joshua D
- Venue
- Molecular Systems Biology
- Published
- 2013-12-03
- Volume
- 9
- Issue
- 1
- Pages
- 712-712
- ISSN
- 1744-4292 (ISSN-L)
- PMC
- PMC3882799
- OpenAlex
- W2101027575
- Cited by
- 428
- References
- 47
- Citations by year
- 2026: 12 · 2025: 37 · 2024: 34 · 2023: 36 · 2022: 48 · 2021: 42 · 2020: 44 · 2019: 39 · 2018: 31 · 2017: 26 · 2016: 30 · 2015: 31 · 2014: 18
- FWCI
- 9.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Systems Biology (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (CA163591-01A1, RC1CA147961, R01CA163591)
- National Institute of General Medical Sciences (P50GM071508)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
- Keywords
- glutamine metabolism, oxidative phosphorylation, ATP production, cancer metabolism, hypoxia, oncogene activation, Ras, Akt, glycolysis, glucose oxidation, TCA cycle, oxygen consumption, energy charge, isotope tracers
- MeSH terms
- Adenosine Triphosphate, Animals, Cell Line, Transformed, Glutamine, Humans, Models, Biological, Neoplasms, Oxidative Phosphorylation, Cell Hypoxia, Cell Line, Tumor, Systems Biology, Mice, Metabolic Networks and Pathways
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