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

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 WLD S 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.

SARM1 deficiency promotes rod and cone photoreceptor cell survival in a model of retinal degeneration

“…mitochondrial decoupling toxin that has been shown to activate SARM1 to induce axon degeneration and cell death in dorsal root ganglia neurons (Summers et al, 2014(Summers et al, , 2020Loreto et al, 2020).…”

SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration

“…Our findings demonstrate that in contrast to canonical necroptotic cell death in which MLKL (mixed lineage kinase domain-like pseudokinase) is the final executioner, there exists a specialized "axonal necroptosis" process in which MLKL works through the SARM1 axon degeneration pathway to drive axon demise. Activated MLKL induces loss of the axon survival factors NMNAT2 and SCG10/ STMN2, known inhibitors of SARM1 activation that are also lost following axotomy, chemotherapy-induced neurotoxicity, and mitochondrial dysfunction (Geisler et al, 2019a;Loreto et al, 2020;Summers et al, 2020;Gilley et al, 2015). Hence, disparate upstream pro-degenerative signals converge on these axon survival factors to activate SARM1.…”

Potent activation of SARM1 by NMN analogue VMN underlies vacor neurotoxicity

“…While NMN activates SARM1 14 and promotes programmed axon death when NMNAT2 is depleted [10][11][12][13] , exogenous NMN does not induce degeneration of uninjured neurites 10 , probably because it is rapidly converted to NAD when NMNAT2 is present, thereby limiting its accumulation. However, we now show that exogenous application of its analogue, VMN, does induce SARM1-dependent death of uninjured DRG neurites ( Fig.…”