Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells
Fendt, Sarah-Maria Bell, Eric L Keibler, Mark A Olenchock, Benjamin A Mayers, Jared R Wasylenko, Thomas M Vokes, Natalie I Guarente, Leonard Vander Heiden, Matthew G Stephanopoulos, Gregory # ×
Nature Communications vol:4 pages:2236
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.