Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells
Open accessAbstract
Reductively metabolized glutamine is a major cellular carbon source for fatty acid synthesis during hypoxia or when mitochondrial respiration is impaired. Yet, a mechanistic understanding of what determines reductive metabolism is missing. Here we identify several cellular conditions where the α-ketoglutarate/citrate ratio is changed due to an altered acetyl-CoA to citrate conversion, and demonstrate that reductive glutamine metabolism is initiated in response to perturbations that result in an increase in the α-ketoglutarate/citrate ratio. Thus, targeting reductive glutamine conversion for a therapeutic benefit might require distinct modulations of metabolite concentrations rather than targeting the upstream signalling, which only indirectly affects the process.
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The increased ratio of α-ketoglutarate to citrate promotes reductive glutamine metabolism and correlates with reductive glutamine's contribution to citrate.
“The increased ratio of α-ketoglutarate to citrate was recently shown to promote reductive glutamine metabolism and it correlated with reductive glutamine’s contribution to citrate (Fendt et al., 2013).”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Fendt et al., 2013
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- Authors
- Fendt, S.-M., Bell, E. L., Keibler, M. A., Olenchock, B. A., Mayers, J. R., Wasylenko, T. M., Vokes, N. I., Guarente, L., Heiden, M. G. V., & Stephanopoulos, G.
- Affiliations
- Massachusetts Institute of Technology (US)
- Brigham and Women's Hospital (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Stephanopoulos, Gregory
- ORCID
- Venue
- Nature Communications
- Published
- 2013-07-31
- Volume
- 4
- Issue
- 1
- Pages
- 2236-2236
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3934748
- OpenAlex
- W2028743750
- Cited by
- 364
- References
- 38
- Citations by year
- 2026: 20 · 2025: 22 · 2024: 29 · 2023: 18 · 2022: 35 · 2021: 43 · 2020: 29 · 2019: 33 · 2018: 22 · 2017: 26 · 2016: 36 · 2015: 24 · 2014: 23 · 2013: 4
- FWCI
- 10.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- PMC
- Funders
- Damon Runyon Cancer Research Foundation
- Wellcome Trust
- Deutsche Forschungsgemeinschaft (P30-CA14051)
- National Institutes of Health
- National Institute on Aging (R01AG015339)
- National Heart, Lung, and Blood Institute (K08HL119355)
- National Cancer Institute (5-P30-CA14051-39, R01CA168653, F32CA132358, R01CA160458, P30CA014051)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- fatty acid synthesis, hypoxia, mitochondrial respiration, cell proliferation
- MeSH terms
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Acetates, Cells, Citric Acid Cycle, Fatty Acids, Glutamine, Humans, Ketoglutaric Acids, Models, Biological, NAD, Nicotinamide Mononucleotide, Oxidation-Reduction, Cell Hypoxia, Protein Serine-Threonine Kinases, Citric Acid, Lactic Acid, Cell Line, Tumor
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