Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death

Summary & key facts

Researchers tested a drug that blocks the mitochondrial pyruvate carrier in brain cells grown in the lab. Blocking this carrier protected those neurons from dying when they were exposed to too much glutamate, the brain’s main excitatory chemical. The blocked carrier did not kill the cells or stop them from making energy. Instead, the cells switched to burning glutamate inside mitochondria for fuel, which lowered the amount of glutamate they released and reduced the damaging feedback loop that causes excitotoxic death. The work links a metabolic pathway in mitochondria to how much glutamate neurons send out and suggests the carrier could be a target for diseases where excess glutamate harms n

Key facts:

• The study used brain cells grown in the lab and chemically blocked the mitochondrial pyruvate carrier, a protein that normally brings pyruvate into mitochondria.
• Blocking this carrier protected neurons from 'excitotoxic' death, which is cell damage caused when too much glutamate overstimulates them.
• Stopping pyruvate entry did not reduce the cells’ ability to make energy, showing the neurons can use other fuels.
• When the carrier was blocked, mitochondria used more glutamate as a fuel. That lowered the amount of glutamate released when the cells were activated.
• Lower glutamate release reduced the positive-feedback loop that normally makes excitotoxic injury worse.
• The authors say this links mitochondrial pyruvate metabolism to glutamate signalling and propose the carrier as a possible therapeutic target for diseases marked by excitotoxicity, but the results are limited to lab-grown neurons and need f

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.

Topics

Metabolism and Genetic Disorders Mitochondrial Function and Pathology Neuroscience and Neuropharmacology Research

Categories

Biochemistry, Genetics and Molecular Biology Life Sciences Molecular Biology

Tags

Amino acid Biochemistry Biology Cell biology Central nervous system Chemistry Enzyme Excitatory postsynaptic potential Excitotoxicity Glutamate receptor Glutamatergic Glutamic acid Inhibitory postsynaptic potential Mitochondrion Neuroscience Neurotransmitter Pyruvate dehydrogenase complex Receptor