title: Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport.
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 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.
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
authors.forename: Chendong
authors.initials: C
authors.lastname: Yang
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
authors.forename: Bookyung
authors.initials: B
authors.lastname: Ko
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Hensley
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
authors.forename: Ajla T
authors.initials: AT
authors.lastname: Wasti
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Sudderth
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Calvaruso
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
authors.forename: Lloyd
authors.initials: L
authors.lastname: Lumata
authors.affiliation: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mitsche
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Rutter
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Merritt
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA; McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA. Electronic address: Ralph.deberardinis@utsouthwestern.edu.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
mesh_terms: D000105:Acetyl Coenzyme A / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001692:Biological Transport; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D019343:Citric Acid / Q000378:metabolism; D002952:Citric Acid Cycle; D003373:Coumaric Acids / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D019289:Pyruvic Acid / Q000378:metabolism*; D013401:Sugar Alcohol Dehydrogenases / Q000378:metabolism; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003373:Coumaric Acids; D005973:Glutamine; C007175:alpha-cyano-4-hydroxycinnamate; D019343:Citric Acid; D000105:Acetyl Coenzyme A; D019289:Pyruvic Acid; D002392:Catechin; C045651:epigallocatechin gallate; D013401:Sugar Alcohol Dehydrogenases; C095946:galactitol 2-dehydrogenase; D005947:Glucose