Impaired disassembly of the axon initial segment restricts mitochondrial entry into damaged axons.

The proteasome is essential for cellular responses to various physiological stressors. However, how proteasome function impacts the stress resilience of regenerative damaged motor neurons remains unclear. Here, we develop a unique mouse model using a regulatory element of the activating transcription factor (Atf3) gene to label mitochondria in a damage‐induced manner while simultaneously genetically disrupting the proteasome. Using this model, we observed that in injury‐induced proteasome‐deficient mouse motor neurons, the increase of mitochondrial influx from soma into axons is inhibited because neurons fail to disassemble ankyrin G, an organizer of the axon initial segment (AIS), in a proteasome‐dependent manner. Further, these motor neurons exhibit amyotrophic lateral sclerosis (ALS)‐like degeneration despite having regenerative potential. Selectively vulnerable motor neurons in SOD1G93A ALS mice, which induce ATF3 in response to pathological damage, also fail to disrupt the AIS, limiting the number of axonal mitochondria at a pre‐symptomatic stage. Thus, damage‐induced proteasome‐sensitive AIS disassembly could be a critical post‐translational response for damaged motor neurons to temporarily transit to an immature state and meet energy demands for axon regeneration or preservation. Synopsis: How the proteasome impacts stress resilience of damaged motor neurons remains unclear. Using unique genetically engineered mice, the proteasome is observed to temporarily dismantle the barrier against mitochondrial axonal entry upon injury to meet energy demands for axon regeneration. Mouse models are developed wherein genetic disruption of the proteosome and mitochondrial labeling co‐occur in response to damage.Motor neurons temporarily dismantle the axon initial segment (AIS) in a proteasome‐dependent manner following injury, permitting increased mitochondrial influx into axons to satisfy the energy demand to drive axon regeneration.Injury‐induced proteasome‐deficient motor neurons in mice fail to dismantle the AIS, which restricts the increase of mitochondria and results in ALS‐like degeneration. [ABSTRACT FROM AUTHOR]