Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation

Neurons in the brain frequently experience glucose shortage and utilize oxidative fuels instead. Here, the authors demonstrate that glucose deprivation drives neuronal expression of the mitochondrial deacetylase sirtuin 3, which stimulates oxidative ATP synthesis in hippocampal nerve terminals to sustain neurotransmission. Neurotransmission is an energetically expensive process that underlies cognition. During intense electrical activity or dietary restrictions, the glucose level in the brain plummets, forcing neurons to utilize alternative fuels. However, the molecular mechanisms of neuronal metabolic plasticity remain poorly understood. Here, we demonstrate that glucose-deprived neurons activate the CREB and PGC1 alpha transcriptional program, which induces expression of the mitochondrial deacetylase Sirtuin 3 (Sirt3) both in vitro and in vivo. We show that Sirt3 localizes to axonal mitochondria and stimulates mitochondrial oxidative capacity in hippocampal nerve terminals. Sirt3 plays an essential role in sustaining synaptic transmission in the absence of glucose by providing metabolic support for the retrieval of synaptic vesicles after release. These results demonstrate that the transcriptional induction of Sirt3 facilitates the metabolic plasticity of synaptic transmission.