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

Chendong Yang, Bookyung Ko, Christopher T. Hensley, Lei Jiang, Ajla T. Wasti, Jiyeon Kim, Jessica Sudderth, MariaAntonietta Calvaruso, Lloyd Lumata, Matthew Mitsche, Jared Rutter, Matthew E. Merritt, Ralph J. DeBerardinis

Research output: Contribution to journalArticle

249 Scopus citations

Abstract

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 themitochondrial 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.

Original languageEnglish (US)
Pages (from-to)414-424
Number of pages11
JournalMolecular cell
Volume56
Issue number3
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Yang, C., Ko, B., Hensley, C. T., Jiang, L., Wasti, A. T., Kim, J., Sudderth, J., Calvaruso, M., Lumata, L., Mitsche, M., Rutter, J., Merritt, M. E., & DeBerardinis, R. J. (2014). Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Molecular cell, 56(3), 414-424. https://doi.org/10.1016/j.molcel.2014.09.025