Mitophagy Eliminates the Accumulation of SARM1 on the Mitochondria, Alleviating Axon Degeneration in Acrylamide Neuropathy

Abstract Background: Sterile-α and toll/interleukin 1 receptor motif containing protein 1 (SARM1) is the central executioner of axon degeneration. Although it has been confirmed to have a mitochondrial targeting sequence and can bind to and stabilize PINK1 on depolarized mitochondria, the biological significance for mitochondrial localization of SARM1 is still unclear. Chronic acrylamide (ACR) intoxication can cause typical pathology of axonal injury, owning the potential to explore the interaction between mitochondria and SARM1 during the latent period of axon destruction.Methods: The expression and the mitochondria distribution of SARM1 were evaluated in in vivo and in vitro ACR neuropathy models. Transmission electron microscopy, immunoblotting, and immunofluorescence were performed to evaluate mitochondrial dynamics and PINK1-dependent mitophagy. LC3 turnover experiment and live cell imaging were conducted to further assess the state of mitophagy flux. In order to verify the effect of mitophagy in SARM1-mediated axon degeneration, low-dose and low-frequency rapamycin was administered in ACR-exposed rats to increase basal autophagy.Results: In a time- and dose-dependent manner, ACR induced peripheral nerve injury in rats and truncated axons of differentiated N2a cell. Moreover, the severity of this axon damage was consistent with the up-regulation of SARM1. SARM1 prominently accumulated on mitochondria, and at the same time mitophagy was activated. Importantly, rapamycin (RAPA) administration eliminated mitochondrial accumulated SARM1 and alleviated SARM1 dependent axonal degeneration.Conclusions: Complementing to the coordinated activity of NMNAT2 and SARM1, mitochondrial localization of SARM1 may be part of the self-limiting molecular mechanisms of Wallerian axon destruction. In the early latent period of axon damage, the mitochondrial localization of SARM1 will help it to be isolated by the mitochondrial network and to be degraded through PINK1-dependent mitophagy to maintain local axon homeostasis. When the mitochondrial quality control mechanisms are broken down, SARM1 will cause irreversible damage for axon degeneration. Moderate autophagy activation can be invoked as potential strategies to alleviate axon degeneration in ACR neuropathy and even other axon degeneration diseases.