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J Cell Biol. 2017 Apr 3;216(4):1091-1105. doi: 10.1083/jcb.201612067. Epub 2017 Mar 2.

Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death.

Author information

1
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.
2
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093.
3
Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
4
Division of Biological Sciences, Neurobiology Section, University of California, San Diego, La Jolla, CA 92093.
5
Department of Pathology, University of California, San Diego, La Jolla, CA 92093.
6
Discovery Research, Teva Pharmaceutical Industries Ltd., West Chester, PA 19380.
7
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093 anmurphy@ucsd.edu.

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.

PMID:
28254829
PMCID:
PMC5379957
DOI:
10.1083/jcb.201612067
[Indexed for MEDLINE]
Free PMC Article

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