RT Journal Article
SR Electronic
T1 Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 683342
DO 10.1101/683342
A1 Andrea Loreto
A1 Ciaran S. Hill
A1 Victoria L. Hewitt
A1 Giuseppe Orsomando
A1 Carlo Angeletti
A1 Jonathan Gilley
A1 Cristiano Lucci
A1 Alvaro Sanchez-Martinez
A1 Alexander J. Whitworth
A1 Laura Conforti
A1 Federico Dajas-Bailador
A1 Michael P. Coleman
YR 2019
UL http://biorxiv.org/content/early/2019/06/27/683342.abstract
AB 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.