Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration

Loreto, Andrea; Hill, Ciaran S.; Hewitt, Victoria L.; Orsomando, Giuseppe; Angeletti, Carlo; Gilley, Jonathan; Lucci, Cristiano; Sanchez-Martinez, Alvaro; Whitworth, Alexander J.; Conforti, Laura; Dajas-Bailador, Federico; Coleman, Michael P.

Abstract

© 2019 The Authors Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinson's disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLDS and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders.

Citation

Loreto, A., Hill, C. S., Hewitt, V. L., Orsomando, G., Angeletti, C., Gilley, J., …Coleman, M. P. (2020). Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration. Neurobiology of Disease, 134, Article 104678. https://doi.org/10.1016/j.nbd.2019.104678

• Journal Article Type: Article
• Acceptance Date: Nov 13, 2019
• Online Publication Date: Nov 15, 2019
• Publication Date: Feb 1, 2020
• Deposit Date: Jan 7, 2020
• Publicly Available Date: Jan 7, 2020
• Journal: Neurobiology of Disease
• Print ISSN: 0969-9961
• Electronic ISSN: 1095-953X
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 134
• Article Number: 104678
• DOI: https://doi.org/10.1016/j.nbd.2019.104678
• Keywords: Neurology
• Public URL: https://nottingham-repository.worktribe.com/output/3548704
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0969996119303535
• Additional Information: This article is maintained by: Elsevier; Article Title: Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration; Journal Title: Neurobiology of Disease; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.nbd.2019.104678; Content Type: article; Copyright: © 2019 The Authors. Published by Elsevier Inc.