Glutamate balances between serving as a neurotransmitter and fueling neuronal mitochondrial metabolism. (A) Synaptic terminal depicting mitochondrial metabolism (Mito) and glutamatergic neurotransmission from synaptic vesicles (SV). Pyruvate enters mitochondria using the MPC and is used in the TCA to produce energy and mitochondrial metabolites. Leucine and β-hydroxybutyrate (β-HB) are also used but only for energy production. Most glutamate is used for transmitter release and high glutamate concentrations may trigger excitotoxicity. (B) With MPC inhibited, pyruvate cannot enter mitochondria. Under these conditions, glutamate fuels the TCA cycle to produce energy and mitochondrial metabolites. Less glutamate is available to neurotransmission, preventing excitotoxicity. aKG, α-ketoglutarate.