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

Author

Listed:
  • Sarah-Maria Fendt

    (Massachusetts Institute of Technology
    Present address: Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium)

  • Eric L. Bell

    (Massachusetts Institute of Technology)

  • Mark A. Keibler

    (Massachusetts Institute of Technology)

  • Benjamin A. Olenchock

    (Koch Institute for Cancer Research, Massachusetts Institute of Technology
    Brigham and Womens Hospital
    Dana-Farber Cancer Institute)

  • Jared R. Mayers

    (Massachusetts Institute of Technology
    Koch Institute for Cancer Research, Massachusetts Institute of Technology)

  • Thomas M. Wasylenko

    (Massachusetts Institute of Technology)

  • Natalie I. Vokes

    (Koch Institute for Cancer Research, Massachusetts Institute of Technology)

  • Leonard Guarente

    (Massachusetts Institute of Technology)

  • Matthew G. Vander Heiden

    (Massachusetts Institute of Technology
    Koch Institute for Cancer Research, Massachusetts Institute of Technology
    Dana-Farber Cancer Institute)

  • Gregory Stephanopoulos

    (Massachusetts Institute of Technology)

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.

Suggested Citation

  • Sarah-Maria Fendt & Eric L. Bell & Mark A. Keibler & Benjamin A. Olenchock & Jared R. Mayers & Thomas M. Wasylenko & Natalie I. Vokes & Leonard Guarente & Matthew G. Vander Heiden & Gregory Stephanopo, 2013. "Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells," Nature Communications, Nature, vol. 4(1), pages 1-11, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3236
    DOI: 10.1038/ncomms3236
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    Cited by:

    1. Natalia Baran & Alessia Lodi & Yogesh Dhungana & Shelley Herbrich & Meghan Collins & Shannon Sweeney & Renu Pandey & Anna Skwarska & Shraddha Patel & Mathieu Tremblay & Vinitha Mary Kuruvilla & Antoni, 2022. "Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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