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Abstract：
The neuromuscular junction (NMJ) is a synapse between motoneurons and skeletal muscles to control motor behavior. Acetylcholine receptors (AChRs) are restricted at the synaptic region for proper neurotransmission. Mutations in the mitochondrial CHCHD10 protein have been identified in multiple neuromuscular disorders; however, the physiological roles of CHCHD10 at NMJs remain elusive. Here, we report that CHCHD10 is highly expressed at the postsynapse of NMJs in skeletal muscles. Muscle conditional knockout CHCHD10 mice showed motor defects, abnormal neuromuscular transmission and NMJ structure. Mechanistically, we found that mitochondrial CHCHD10 is required for ATP production, which facilitates AChR expression and promotes agrin-induced AChR clustering. Importantly, ATP could effectively rescue the reduction of AChR clusters in the CHCHD10-ablated muscles. Our study elucidates a novel physiological role of CHCHD10 at the peripheral synapse. It suggests that mitochondria dysfunction contributes to neuromuscular pathogenesis.
摘要：
神经肌肉接头（NMJ）是运动神经元和骨骼肌之间的突触，用于控制运动行为。乙酰胆碱受体（AChR）在突触区域受到限制，以进行适当的神经传递。线粒体CHCHD10蛋白的突变已在多种神经肌肉疾病中被发现；然而，CHCHD10在NMJ中的生理作用仍然难以捉摸。这里,我们报道CHCHD10在骨骼肌NMJ的突触后高表达。肌肉条件性敲除CHCHD10小鼠表现出运动缺陷，神经肌肉传递和NMJ结构异常。机械上,我们发现线粒体CHCHD10是ATP产生所必需的，这促进了AChR的表达并促进了agrin诱导的AChR聚类。重要的是,ATP可以有效地挽救CHCHD10消融肌肉中AChR簇的减少。我们的研究阐明了CHCHD10在外周突触中的新生理作用。这表明线粒体功能障碍有助于神经肌肉的发病机制。
