Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation

Author:

Tiwari Anupama1ORCID,Hashemiaghdam Arsalan1ORCID,Laramie Marissa A.1ORCID,Maschi Dario1ORCID,Haddad Tristaan1ORCID,Stunault Marion I.1ORCID,Bergom Carmen23ORCID,Javaheri Ali45ORCID,Klyachko Vitaly1ORCID,Ashrafi Ghazaleh16ORCID

Affiliation:

1. Washington University School of Medicine 1 Department of Cell Biology and Physiology, , St. Louis, MO, USA

2. Washington University School of Medicine 2 Department of Radiation Oncology, , St. Louis, MO, USA

3. Washington University School of Medicine 3 Alvin J. Siteman Cancer Center, , St. Louis, MO, USA

4. Washington University School of Medicine 4 Division of Cardiology, Department of Medicine, , St. Louis, MO, USA

5. John Cochran VA Hospital 6 , St. Louis, MO, USA

6. Washington University School of Medicine 5 Needleman Center for Neurometabolism and Axonal Therapeutics, , St. Louis, MO, USA

Abstract

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 PGC1α 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.

Funder

Washington University Center for Cellular Imaging

National Cancer Institute

Siteman Cancer Center

Institute of Clinical and Translational Sciences

National Center for Research Resources

National Institutes of Health

Washington University Institute of Clinical and Translational Sciences

National Center for Advancing Translational Sciences

McDonnell Institute for Cellular Neurobiology

Whitehall Foundation

National Institute of General Medical Sciences

National Institute of Neurological Disorders and Stroke

National Heart, Lung, and Blood Institute

Children’s Discovery Institute

St. Louis Children’s Hospital

Diabetes Research Center

Longer Life Foundation

Publisher

Rockefeller University Press

Subject

Cell Biology

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1. Sugar-free synapses run on mitochondrial Sirtuin 3;Journal of Cell Biology;2023-12-13

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