Loss of mitochondrial protein CHCHD10 in skeletal muscle causes neuromuscular junction impairment

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  • Yatao Xiao
    The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang, China 310003
  • Jianmin Zhang
    The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang, China 310003
  • Xiaoqiu Shu
    The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang, China 310003
  • Lei Bai
    The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang, China 310003
  • Wentao Xu
    The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang, China 310003
  • Ailian Wang
    The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang, China 310003
  • Aizhong Chen
    The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang, China 310003
  • Wen-Yo Tu
    The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang, China 310003
  • Jianwen Wang
    The First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China 310003
  • Kejing Zhang
    The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang, China 310003
  • Benyan Luo
    The First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China 310003
  • Chengyong Shen
    The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang, China 310003

説明

<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>

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