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

Nat Commun. 2013;4:2236. doi: 10.1038/ncomms3236.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / metabolism
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cells / metabolism*
  • Citric Acid / metabolism*
  • Citric Acid Cycle
  • Fatty Acids / metabolism
  • Glutamine / metabolism*
  • Humans
  • Ketoglutaric Acids / metabolism*
  • Lactic Acid / metabolism
  • Models, Biological
  • NAD / metabolism
  • Nicotinamide Mononucleotide / metabolism
  • Oxidation-Reduction
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase


  • Acetates
  • Fatty Acids
  • Ketoglutaric Acids
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Glutamine
  • NAD
  • Nicotinamide Mononucleotide
  • Citric Acid
  • Lactic Acid
  • Protein-Serine-Threonine Kinases