Mitochondrial Localization of SARM1 in Acrylamide Intoxication Induces Mitophagy and Limits Neuropathy

Sterile alpha and toll/interleukin 1 receptor motif-containing protein 1 (SARM1) is the defining molecule and central executioner of programmed axon death, also known as Wallerian degeneration. SARM1 has a mitochondrial targeting sequence, and it can bind to and stabilize PTEN-induced putative kinase 1 (PINK1) for mitophagy induction, but the deletion of the mitochondrial localization sequence is found to disrupt the mitochondrial localization of SARM1 in neurons without altering its ability to promote axon degeneration after axotomy. The biological significance of SARM1 mitochondrial localization remains elusive. In this study, we observed that the pro-degeneration factor, SARM1, was upregulated in acrylamide (ACR) neuropathy, a slow, Wallerian-like, programmed axonal death process. The upregulated SARM1 accumulated on mitochondria, interfered with mitochondrial dynamics, and activated PINK1-mediated mitophagy. Importantly, rapamycin (RAPA) intervention eliminated mitochondrial accumulation of SARM1 and partly attenuated ACR neuropathy. Thus, mitochondrial localization of SARM1 may contribute to its clearance through the SARM1-PINK1 mitophagy pathway, which inhibits axonal degeneration through a negative feedback loop. The mitochondrial localization of SARM1 complements the coordinated activity of the pro-survival factor, nicotinamide mononucleotide adenyltransferase 2 (NMNAT2), and SARM1 and is part of the self-limiting molecular mechanisms underpinning programmed axon death in ACR neuropathy.

Automated summary

This study reveals the importance of mitochondrial localization of SARM1 in programmed axon death. Mitochondrial accumulation of SARM1 interferes with mitochondrial dynamics and activates PINK1-mediated mitophagy, contributing to axonal degeneration. Rapamycin intervention eliminates mitochondrial accumulation of SARM1 and partially attenuates neuropathy. The findings suggest that mitochondrial localization of SARM1 plays a role in its clearance through the SARM1-PINK1 mitophagy pathway.