Glutamine Oxidation Maintains the TCA Cycle and Cell Survival during Impaired Mitochondrial Pyruvate Transport

• Published in: Molecular cell Vol. 56; no. 3; pp. 414 - 424
• Main Authors: Yang, Chendong, Ko, Bookyung, Hensley, Christopher T., Jiang, Lei, Wasti, Ajla T., Kim, Jiyeon, Sudderth, Jessica, Calvaruso, Maria Antonietta, Lumata, Lloyd, Mitsche, Matthew, Rutter, Jared, Merritt, Matthew E., DeBerardinis, Ralph J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.11.2014
• Subjects: acetyl coenzyme A; Acetyl Coenzyme A - biosynthesis; Animals; Antineoplastic Agents - pharmacology; Biological Transport; Catechin - analogs & derivatives; Catechin - pharmacology; cell cycle; Cell Line, Tumor; Cell Survival; cell viability; Citric Acid - metabolism; Citric Acid Cycle; Coumaric Acids - pharmacology; cytotoxicity; glucose; Glucose - metabolism; glutamate dehydrogenase; glutamine; Glutamine - metabolism; Humans; Lipid Metabolism; Male; metabolism; Mice, Nude; mitochondria; Mitochondria - metabolism; oxidation; Oxidation-Reduction; pyruvic acid; Pyruvic Acid - metabolism; Sugar Alcohol Dehydrogenases - metabolism; tricarboxylic acid cycle; Tumor Burden; Xenograft Model Antitumor Assays
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2014.09.025

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. [Display omitted] •Mitochondria produce acetyl-CoA from glutamine during MPC inhibition•Alanine synthesis is suppressed during MPC inhibition•MPC inhibition activates GDH to supply pools of TCA cycle intermediates•GDH supports cell survival during periods of MPC inhibition Cancer cells import pyruvate into their mitochondria and convert it to acetyl-CoA for bioenergetics and biosynthesis. Yang et al. demonstrate that inhibition of mitochondrial pyruvate transport activates a compensatory pathway in which intramitochondrial glutamine metabolism produces pyruvate and acetyl-CoA. Inhibiting this compensatory pathway limits cell survival and tumor growth.