Neuromuscular junction mitochondrial enrichment: a “double-edged sword” underlying the selective motor neuron vulnerability in amyotrophic lateral sclerosis

摘要

Motor neuronsare highly polarized cells, with long axons thatextend to morethan 1 min theadult human. Theaxons furtherarborizeinto aspecialized synapticcompartment, the motor unit,containing up to 2000 neuromuscular junctions (NMJs). Whilethesize of other neuronalsynapsescan be up to 1 μm, the NMJ is much largerand can reach 10–30 μm(Jonesetal., 2017). The vastsize ofthe motor unit requires motorneurons to evolutionally adaptand supply this distal portionwith asufficientamount ofATP,as wellas to replenish theaxonal protein poolin orderto maintain their synapses. To address its substantialenergetic needs, the NMJ isenriched with a vast network ofmitochondria. This is supportedby ultrastructuralstudies using electron and confocalmicroscopy, which revealed that only ~50%ofactivesynapses in theadult rodentcentralnervous system(CNS)contain anymitochondria, whereasallNMJsareenriched with atightly packed mitochondrial network (Misgeld andSchwarz, 2017; Altman etal., 2019). The mechanisms leading to this distinctenrichment,as wellas its implicationsand functionalmeaning in thecontext of neurodegeneration, remain poorly understood. Here, we discussand suggesta possibleexplanation for howthe mitochondrialenrichment ofthe NMJcan berelevant to theselective vulnerability ofmotor neurons inmotor neuron diseases,and in particularamyotrophiclateralsclerosis (ALS).