Repository logo
 

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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Hill, Ciaran S 
Hewitt, Victoria L 
Orsomando, Giuseppe 
Angeletti, Carlo 

Abstract

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.

Description

Keywords

Axon degeneration, Mitochondrial dysfunction, NMNAT2, Parkinson's disease, Pink1, SARM1, Wallerian degeneration, Animals, Armadillo Domain Proteins, Axons, Cytoskeletal Proteins, Drosophila, Male, Membrane Potential, Mitochondrial, Mice, Inbred C57BL, Mitochondria, Nicotinamide-Nucleotide Adenylyltransferase, Wallerian Degeneration

Journal Title

Neurobiol Dis

Conference Name

Journal ISSN

0969-9961
1095-953X

Volume Title

134

Publisher

Elsevier BV

Rights

All rights reserved
Sponsorship
Medical Research Council (MC_UP_1501/1)
Medical Research Council (MC_UU_00015/6)
Medical Research Council (MR/N004582/1)
Wellcome Trust (210904/Z/18/Z)
Medical Research Council (MC_UU_00015/7)
Relationships
Is derived from: