Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission

ABSTRACT Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep, intense circuit activity, or dietary restrictions, posing significant metabolic stress. Here, we demonstrate that the mammalian brain utilizes pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability within a neuron and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation which in turn modulates mitochondrial pyruvate uptake. Importantly, our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in synaptic transmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval, functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of synaptic transmission in hippocampal terminals. HIGHLIGHTS Serum pyruvate is taken up by the brain and efficiently oxidized in the TCA cycle. The mitochondrial pyruvate carrier (MPC) is essential for presynaptic energy metabolism. Acetylation of the MPC complex modulates mitochondrial pyruvate uptake. MPC activity regulates the release and retrieval of synaptic vesicles in nerve terminals.