Oligodendrocytes Enhance Axonal Energy Metabolism by Deacetylation of Mitochondrial Proteins Through Transcellular Delivery of SIRT2

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2021 Sep 10

PMID 34506725

Citations 66

Authors

Kelly A Chamberlain

Ning Huang

Yuxiang Xie

Francesca LiCausi

Sunan Li

Yan Li

Zu-Hang Sheng

Affiliations

Soon will be listed here.

Abstract

Neurons require mechanisms to maintain ATP homeostasis in axons, which are highly vulnerable to bioenergetic failure. Here, we elucidate a transcellular signaling mechanism by which oligodendrocytes support axonal energy metabolism via transcellular delivery of NAD-dependent deacetylase SIRT2. SIRT2 is undetectable in neurons but enriched in oligodendrocytes and released within exosomes. By deleting sirt2, knocking down SIRT2, or blocking exosome release, we demonstrate that transcellular delivery of SIRT2 is critical for axonal energy enhancement. Mass spectrometry and acetylation analyses indicate that neurons treated with oligodendrocyte-conditioned media from WT, but not sirt2-knockout, mice exhibit strong deacetylation of mitochondrial adenine nucleotide translocases 1 and 2 (ANT1/2). In vivo delivery of SIRT2-filled exosomes into myelinated axons rescues mitochondrial integrity in sirt2-knockout mouse spinal cords. Thus, our study reveals an oligodendrocyte-to-axon delivery of SIRT2, which enhances ATP production by deacetylating mitochondrial proteins, providing a target for boosting axonal bioenergetic metabolism in neurological disorders.

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