title: Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells.
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.
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Sarah-Maria
authors.initials: SM
authors.lastname: Fendt
authors.forename: Eric L
authors.initials: EL
authors.lastname: Bell
authors.forename: Mark A
authors.initials: MA
authors.lastname: Keibler
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Olenchock
authors.forename: Jared R
authors.initials: JR
authors.lastname: Mayers
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wasylenko
authors.forename: Natalie I
authors.initials: NI
authors.lastname: Vokes
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.forename: Gregory
authors.initials: G
authors.lastname: Stephanopoulos
mesh_terms: D000085:Acetates / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002477:Cells / Q000378:metabolism*; D019343:Citric Acid / Q000378:metabolism*; D002952:Citric Acid Cycle; D005227:Fatty Acids / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D007656:Ketoglutaric Acids / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D008954:Models, Biological; D009243:NAD / Q000378:metabolism; D009537:Nicotinamide Mononucleotide / Q000378:metabolism; D010084:Oxidation-Reduction; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: D000085:Acetates; D005227:Fatty Acids; D007656:Ketoglutaric Acids; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D005973:Glutamine; D009243:NAD; D009537:Nicotinamide Mononucleotide; D019343:Citric Acid; D019344:Lactic Acid; D017346:Protein Serine-Threonine Kinases
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