Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation

Tiwari, A.; Hashemiaghdam, A.; Laramie, M.; Maschi, D.; Haddad, T.; Stunault, M.; Bergom, C.; Javaheri, A.; Klyachko, V.; Ashrafi, G.

doi:10.1101/2023.03.08.531724

bioRxiv · 10.1101/2023.03.08.531724

Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation

Tiwari, A.·Hashemiaghdam, A.·Laramie, M.·Maschi, D.·Haddad, T.·Stunault, M.·Bergom, C.·Javaheri, A.·Klyachko, V.·Ashrafi, G.

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Abstract

Neurotransmission is an energetically expensive process that underlies cognition. During intense electrical activity or dietary restrictions, glucose levels in the brain plummet, 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 transcriptional program that induces the 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 powering the retrieval of synaptic vesicles after release. These results demonstrate that the transcriptional induction of Sirt3 ensures the metabolic plasticity of synaptic transmission. HighlightsO_LIGlucose deprivation drives transcriptional reprogramming of neuronal metabolism via CREB and PGC1. C_LIO_LIGlucose or food deprivation trigger the neuronal expression of mitochondrial deacetylase sirtuin 3 (Sirt3) both in vitro and in vivo. C_LIO_LISirt3 stimulates oxidative ATP synthesis in nerve terminals. C_LIO_LISirt3 sustains the synaptic vesicle cycle in the absence of glucose. C_LI

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Tiwari, A., Hashemiaghdam, A., Laramie, M., Maschi, D., Haddad, T., Stunault, M., Bergom, C., Javaheri, A., Klyachko, V., Ashrafi, G.. 2023-03-10. Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation. https://doi.org/10.1101/2023.03.08.531724

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