Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death

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


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.

MeSH terms

  • Animals
  • Cell Death / physiology*
  • Energy Metabolism / physiology
  • Glutamic Acid / metabolism
  • Membrane Transport Proteins / metabolism*
  • Mitochondria / metabolism*
  • Mitochondrial Proteins
  • Monocarboxylic Acid Transporters
  • Neurodegenerative Diseases / metabolism
  • Neurons / metabolism*
  • Neurons / physiology*
  • Oxidation-Reduction
  • Pyruvic Acid / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Solute Carrier Proteins


  • Membrane Transport Proteins
  • Mitochondrial Proteins
  • Monocarboxylic Acid Transporters
  • Mpc1 protein, rat
  • Solute Carrier Proteins
  • Glutamic Acid
  • Pyruvic Acid