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

Motor neurons are highly polarized cells,with long axons that extend to more than 1 m in the adult human.The axons further arborize into a specialized synaptic compartment,the motor unit,containing up to 2000neuromuscular junctions (NMJs).While the size of other neuronal synapses can be up to1μm,the NMJ is much larger and can reach10-30μm (Jones et al.,2017).The vast size of the motor unit requires motor neurons to evolutionally adapt and supply this distal portion with a sufficient amount of ATP,as well as to replenish the axonal protein pool in order to maintain their synapses.To address its substantial energetic needs,the NMJ is enriched with a vast network of mitochondria.This is supported by ultrastructural studies using electron and confocal microscopy,which revealed that only～50%of active synapses