MitoCare Center for Mitochondrial Imaging Research and Diagnostics, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
Center for Genetic Medicine Research, Children's National Health System, 111 Michigan Avenue Northwest, Washington, DC 20010, USA; Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC 20052, USA.
Cell Rep. 2019 Oct 29;29(5):1274-1286.e6. doi: 10.1016/j.celrep.2019.09.063.
Muscle function is regulated by Ca, which mediates excitation-contraction coupling, energy metabolism, adaptation to exercise, and sarcolemmal repair. Several of these actions rely on Ca delivery to the mitochondrial matrix via the mitochondrial Ca uniporter, the pore of which is formed by mitochondrial calcium uniporter (MCU). MCU's gatekeeping and cooperative activation are controlled by MICU1. Loss-of-protein mutation in MICU1 causes a neuromuscular disease. To determine the mechanisms underlying the muscle impairments, we used MICU1 patient cells and skeletal muscle-specific MICU1 knockout mice. Both these models show a lower threshold for MCU-mediated Ca uptake. Lack of MICU1 is associated with impaired mitochondrial Ca uptake during excitation-contraction, aerobic metabolism impairment, muscle weakness, fatigue, and myofiber damage during physical activity. MICU1 deficit compromises mitochondrial Ca uptake during sarcolemmal injury, which causes ineffective repair of the damaged myofibers. Thus, dysregulation of mitochondrial Ca uptake hampers myofiber contractile function, likely through energy metabolism and membrane repair.
肌肉功能受 Ca 调节，Ca 介导兴奋-收缩偶联、能量代谢、运动适应和肌膜修复。这些作用中的一些依赖于通过线粒体 Ca 单向转运体（MCU）将 Ca 递送至线粒体基质。MCU 的门控和协同激活由 MCU1 调节。MCU1 的蛋白丢失突变导致神经肌肉疾病。为了确定肌肉损伤的机制，我们使用了 MCU1 患者细胞和骨骼肌特异性 MCU1 敲除小鼠。这两种模型均显示出较低的 MCU 介导的 Ca 摄取阈值。缺乏 MCU1 与兴奋-收缩时的线粒体 Ca 摄取受损、有氧代谢受损、肌肉无力、疲劳和体力活动时的肌纤维损伤有关。在肌膜损伤期间，MICU1 缺陷会损害线粒体 Ca 的摄取，从而导致受损肌纤维的修复无效。因此，线粒体 Ca 摄取的失调会损害肌纤维的收缩功能，可能通过能量代谢和膜修复。
