title: Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death.
abstract: Glutamate is the dominant excitatory neurotransmitter in the brain, but under conditions of metabolic stress it can accumulate to excitotoxic levels. Although pharmacologic modulation of excitatory amino acid receptors is well studied, minimal consideration has been given to targeting mitochondrial glutamate metabolism to control neurotransmitter levels. Here we demonstrate that chemical inhibition of the mitochondrial pyruvate carrier (MPC) protects primary cortical neurons from excitotoxic death. Reductions in mitochondrial pyruvate uptake do not compromise cellular energy metabolism, suggesting neuronal metabolic flexibility. Rather, MPC inhibition rewires mitochondrial substrate metabolism to preferentially increase reliance on glutamate to fuel energetics and anaplerosis. Mobilizing the neuronal glutamate pool for oxidation decreases the quantity of glutamate released upon depolarization and, in turn, limits the positive-feedback cascade of excitotoxic neuronal injury. The finding links mitochondrial pyruvate metabolism to glutamatergic neurotransmission and establishes the MPC as a therapeutic target to treat neurodegenerative diseases characterized by excitotoxicity.
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Ajit S
authors.identifier: 0000-0002-2528-9651
authors.initials: AS
authors.lastname: Divakaruni
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Martina
authors.initials: M
authors.lastname: Wallace
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Caodu
authors.initials: C
authors.lastname: Buren
authors.affiliation: Division of Biological Sciences, Neurobiology Section, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Kelly
authors.initials: K
authors.lastname: Martyniuk
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Andreyev
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Edward
authors.initials: E
authors.lastname: Li
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Jerel A
authors.initials: JA
authors.lastname: Fields
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Thekla
authors.initials: T
authors.lastname: Cordes
authors.affiliation: Discovery Research, Teva Pharmaceutical Industries Ltd., West Chester, PA 19380.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Reynolds
authors.affiliation: Division of Biological Sciences, Neurobiology Section, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Bloodgood
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Lynn A
authors.identifier: 0000-0002-8610-1042
authors.initials: LA
authors.lastname: Raymond
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Metallo
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093 anmurphy@ucsd.edu.
authors.forename: Anne N
authors.identifier: 0000-0002-5222-9902
authors.initials: AN
authors.lastname: Murphy
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins; D027501:Monocarboxylic Acid Transporters; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000502:physiology*; D010084:Oxidation-Reduction; D019289:Pyruvic Acid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000070590:Solute Carrier Proteins
chemical_list: D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D027501:Monocarboxylic Acid Transporters; C000629174:Mpc1 protein, rat; D000070590:Solute Carrier Proteins; D018698:Glutamic Acid; D019289:Pyruvic Acid