Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport

Mol Cell. 2014 Nov 6;56(3):414-424. doi: 10.1016/j.molcel.2014.09.025. Epub 2014 Oct 21.


Alternative modes of metabolism enable cells to resist metabolic stress. Inhibiting these compensatory pathways may produce synthetic lethality. We previously demonstrated that glucose deprivation stimulated a pathway in which acetyl-CoA was formed from glutamine downstream of glutamate dehydrogenase (GDH). Here we show that import of pyruvate into the mitochondria suppresses GDH and glutamine-dependent acetyl-CoA formation. Inhibiting the mitochondrial pyruvate carrier (MPC) activates GDH and reroutes glutamine metabolism to generate both oxaloacetate and acetyl-CoA, enabling persistent tricarboxylic acid (TCA) cycle function. Pharmacological blockade of GDH elicited largely cytostatic effects in culture, but these effects became cytotoxic when combined with MPC inhibition. Concomitant administration of MPC and GDH inhibitors significantly impaired tumor growth compared to either inhibitor used as a single agent. Together, the data define a mechanism to induce glutaminolysis and uncover a survival pathway engaged during compromised supply of pyruvate to the mitochondria.

Publication types

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

MeSH terms

  • Acetyl Coenzyme A / biosynthesis
  • Animals
  • Antineoplastic Agents / pharmacology
  • Biological Transport
  • Catechin / analogs & derivatives
  • Catechin / pharmacology
  • Cell Line, Tumor
  • Cell Survival*
  • Citric Acid / metabolism
  • Citric Acid Cycle*
  • Coumaric Acids / pharmacology
  • Glucose / metabolism
  • Glutamine / metabolism*
  • Humans
  • Lipid Metabolism
  • Male
  • Mice, Nude
  • Mitochondria / metabolism
  • Oxidation-Reduction
  • Pyruvic Acid / metabolism*
  • Sugar Alcohol Dehydrogenases / metabolism
  • Tumor Burden
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Coumaric Acids
  • Glutamine
  • alpha-cyano-4-hydroxycinnamate
  • Citric Acid
  • Acetyl Coenzyme A
  • Pyruvic Acid
  • Catechin
  • epigallocatechin gallate
  • Sugar Alcohol Dehydrogenases
  • galactitol 2-dehydrogenase
  • Glucose