Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges

The impact of mitochondrial protein acetylation status on neuronal function and vulnerability to neurological disorders is unknown. Here we show that the mitochondrial protein deacetylase SIRT3 mediates adaptive responses of neurons to bioenergetic, oxidative, and excitatory stress. Cortical neurons lacking SIRT3 exhibit heightened sensitivity to glutamate-induced calcium overload and excitotoxicity and oxidative and mitochondrial stress; AAV-mediated Sirt3 gene delivery restores neuronal stress resistance. In models relevant to Huntington’s disease and epilepsy, Sirt3−/− mice exhibit increased vulnerability of striatal and hippocampal neurons, respectively. SIRT3 deficiency results in hyperacetylation of several mitochondrial proteins, including superoxide dismutase 2 and cyclophilin D. Running wheel exercise increases the expression of Sirt3 in hippocampal neurons, which is mediated by excitatory glutamatergic neurotransmission and is essential for mitochondrial protein acetylation homeostasis and the neuroprotective effects of running. Our findings suggest that SIRT3 plays pivotal roles in adaptive responses of neurons to physiological challenges and resistance to degeneration. [Display omitted] •Exercise and glutamatergic signaling induce SIRT3 expression in cortical neurons•SIRT3 deacetylates SOD2 and cyclophilin D in neuronal mitochondria•SIRT3 prevents neuronal death in mouse models of epilepsy and Huntington’s disease•SIRT3 mediates adaptive responses of neurons to excitotoxic and metabolic stress Cheng et al. find that neurons lacking the mitochondrial deacetylase SIRT3 are more vulnerable to dysfunction and degeneration in mouse models of epilepsy and Huntington’s disease. Exercise and synaptic activity induce hippocampal SIRT3 expression to modulate mitochondrial protein acetylation and bolster neuronal resistance to oxidative stress and apoptosis.