Mitophagy suppresses motor neuron necroptotic mitochondrial damage and alleviates necroptosis that converges to SARM1 in acrylamide ‐induced dying‐back neuropathy

We propose upstream necroptotic mitochondrial damage initiates SARM1-dependent core axonal destruction program in acrylamide (ACR)-induced dying-back neuropathy. Rapamycin (RAPA) intervention enhanced mitophagic flux and timely removed damage-related molecules that gathered on mitochondria, for instance, phosphorylation-activated MLKL. Thus, mitophagy inhibited mitochondrial damage that was associated with multiple necroptotic pathways, alleviating ACR-induced neuropathy. AbstractAcrylamide (ACR), a common industrial ingredient that is also found in many foodstuffs, induces dying-back neuropathy in humans and animals. However, the mechanisms remain poorly understood. Sterile alpha and toll/interleukin 1 receptor motif-containing protein 1 (SARM1) is the central determinant of axonal degeneration and has crosstalk with different cell death programs to determine neuronal survival. Herein, we illustrated the role of SARM1 in ACR-induced dying-back neuropathy. We further demonstrated the upstream programmed cell death mechanism of this SARM1-dependent process. Spinal cord motor neurons that were induced to overexpress SARM1 underwent necroptosis rather than apoptosis in ACR neuropathy. Mechanically, non-canonical necroptotic pathways mediated mitochondrial permeability transition pore (mPTP) opening, reactive oxygen species (ROS) production, and mitochondrial fission. What's more, the final executioner of necroptosis, phosphorylation-activated mixed lineage kinase domain-like pro...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research