State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Department of Spine Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University Medical School, Nanjing University, Nanjing, China.
Jiangsu Key Laboratory of Molecular Medicine & Chemistry and Biomedicine Innovation Center, Medical School of Nanjing University, Nanjing, China.
Nat Commun. 2022 Feb 16;13(1):894. doi: 10.1038/s41467-022-28557-5.
Mitochondrial proteolysis is an evolutionarily conserved quality-control mechanism to maintain proper mitochondrial integrity and function. However, the physiological relevance of stress-induced impaired mitochondrial protein quality remains unclear. Here, we demonstrate that LONP1, a major mitochondrial protease resides in the matrix, plays a role in controlling mitochondrial function as well as skeletal muscle mass and strength in response to muscle disuse. In humans and mice, disuse-related muscle loss is associated with decreased mitochondrial LONP1 protein. Skeletal muscle-specific ablation of LONP1 in mice resulted in impaired mitochondrial protein turnover, leading to mitochondrial dysfunction. This caused reduced muscle fiber size and strength. Mechanistically, aberrant accumulation of mitochondrial-retained protein in muscle upon loss of LONP1 induces the activation of autophagy-lysosome degradation program of muscle loss. Overexpressing a mitochondrial-retained mutant ornithine transcarbamylase (ΔOTC), a known protein degraded by LONP1, in skeletal muscle induces mitochondrial dysfunction, autophagy activation, and cause muscle loss and weakness. Thus, these findings reveal a role of LONP1-dependent mitochondrial protein quality-control in safeguarding mitochondrial function and preserving skeletal muscle mass and strength, and unravel a link between mitochondrial protein quality and muscle mass maintenance during muscle disuse.
线粒体蛋白水解是一种进化上保守的质量控制机制，可维持线粒体的适当完整性和功能。然而，应激诱导的线粒体蛋白质量受损的生理相关性尚不清楚。在这里，我们证明了主要存在于基质中的线粒体蛋白酶 LONP1 在控制线粒体功能以及骨骼肌质量和力量方面发挥作用，以响应肌肉废用。在人和小鼠中，与废用相关的肌肉损失与线粒体 LONP1 蛋白减少有关。在小鼠中特异性敲除骨骼肌中的 LONP1 会导致线粒体蛋白周转受损，导致线粒体功能障碍。这导致肌肉纤维大小和强度降低。在机制上，由于 LONP1 缺失导致线粒体保留蛋白的异常积累，从而引发肌肉损失的自噬-溶酶体降解程序的激活。在骨骼肌中过表达已知被 LONP1 降解的线粒体保留突变型鸟氨酸转氨甲酰酶（ΔOTC）会导致线粒体功能障碍、自噬激活，并导致肌肉损失和无力。因此，这些发现揭示了 LONP1 依赖性线粒体蛋白质量控制在保护线粒体功能和维持骨骼肌质量和力量方面的作用，并揭示了在肌肉废用期间线粒体蛋白质量与肌肉质量维持之间的联系。
