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

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 and Gregory Stephanopoulos ()
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Sarah-Maria Fendt: Massachusetts Institute of Technology
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
Jared R. Mayers: 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
Gregory Stephanopoulos: Massachusetts Institute of Technology

Nature Communications, 2013, vol. 4, issue 1, 1-11

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3236

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