Cited by 364Cancer, Hypoxia, and MetabolismCancer, Lipids, and MetabolismAmino Acid Enzymes and Metabolism

Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells

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Fendt, Sarah-Maria, Bell, Eric L., Keibler, Mark A., Olenchock, Benjamin A., Mayers, Jared R., Wasylenko, Thomas M., Vokes, Natalie I., Guarente, Leonard +2 more·2013·Nature Communications

Abstract

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).”

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  1. [15]Dickman SR The Enzymes (chapter aconitase) Academic Press New York 1961

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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
Venue
Nature Communications
Published
2013-07-31
Volume
4
Issue
1
Pages
2236-2236
ISSN
2041-1723 (ISSN-L)
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
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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