Cellular homeostasis requires tight coordination between nucleus and mitochondria, organelles that each possesses their own genomes. Disrupted mitonuclear communication has been found to be implicated in many aging processes. However, little is known about mitonuclear signaling regulator in sarcopenia which is a major contributor to the risk of poor health‐related quality of life, disability, and premature death in older people. High‐temperature requirement protein A2 (HtrA2/Omi) is a mitochondrial protease and plays an important role in mitochondrial proteostasis. HtrA2mnd2(−/−) mice harboring protease‐deficient HtrA2/Omi Ser276Cys missense mutants exhibit premature aging phenotype. Additionally, HtrA2/Omi has been established as a signaling regulator in nervous system and tumors. We therefore asked whether HtrA2/Omi participates in mitonuclear signaling regulation in muscle degeneration. Using motor functional, histological, and molecular biological methods, we characterized the phenotype of HtrA2mnd2(−/−) muscle. Furthermore, we isolated the gastrocnemius muscle of HtrA2mnd2(−/−) mice and determined expression of genes in mitochondrial unfolded protein response (UPRmt), mitohormesis, electron transport chain (ETC), and mitochondrial biogenesis. Here, we showed that HtrA2/Omi protease deficiency induced denervation‐independent skeletal muscle degeneration with sarcopenia phenotypes. Despite mitochondrial hypofunction, upregulation of UPRmt and mitohormesis‐related genes and elevated total reactive oxygen species (ROS) production were not observed in HtrA2mnd2(−/−) mice, contrary to previous assumptions that loss of protease activity of HtrA2/Omi would lead to mitochondrial dysfunction as a result of proteostasis disturbance and ROS burst. Instead, we showed that HtrA2/Omi protease deficiency results in different changes between the expression of nuclear DNA‐ and mitochondrial DNA‐encoded ETC subunits, which is in consistent with their transcription factors, nuclear respiratory factors 1 and 2, and coactivator peroxisome proliferator‐activated receptor γ coactivator 1α. These results reveal that loss of HtrA2/Omi protease activity induces mitonuclear imbalance via differential regulation of mitochondrial biogenesis in sarcopenia. The novel mechanistic insights may be of importance in developing new therapeutic strategies for sarcopenia.

中文翻译：

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高温需求蛋白A2蛋白酶活性的丧失通过肌肉减少症中线粒体生物发生的差异调节诱导线粒体失衡

细胞稳态需要细胞核和线粒体之间的紧密协调，线粒体和细胞器各自拥有自己的基因组。已发现中断的线粒体核通讯与许多衰老过程有关。然而，关于肌肉减少症中的线粒体信号调节剂知之甚少，这是导致老年人健康相关生活质量差、残疾和过早死亡风险的主要因素。高温需求蛋白 A2 (HtrA2/Omi) 是一种线粒体蛋白酶，在线粒体蛋白质稳态中起重要作用。携带蛋白酶缺陷型 HtrA2/Omi Ser276Cys 错义突变体的 HtrA2mnd2(-/-) 小鼠表现出过早衰老表型。此外，HtrA2/Omi 已被确定为神经系统和肿瘤中的信号调节剂。因此，我们询问 HtrA2/Omi 是否参与肌肉退化中的线粒体信号调节。使用运动功能、组织学和分子生物学方法，我们表征了 HtrA2mnd2(-/-) 肌肉的表型。此外，我们分离了 HtrA2mnd2(-/-) 小鼠的腓肠肌，并确定了线粒体未折叠蛋白反应 (UPRmt)、有丝分裂、电子传递链 (ETC) 和线粒体生物发生中基因的表达。在这里，我们发现 HtrA2/Omi 蛋白酶缺乏诱导具有肌肉减少症表型的非神经支配的骨骼肌变性。尽管线粒体功能低下，但在 HtrA2mnd2(-/-) 小鼠中未观察到 UPRmt 和线粒体相关基因的上调和总活性氧 (ROS) 的产生。与之前的假设相反，即 HtrA2/Omi 蛋白酶活性的丧失会导致线粒体功能障碍，这是蛋白质稳态紊乱和 ROS 爆发的结果。相反，我们发现 HtrA2/Omi 蛋白酶缺乏导致核 DNA 和线粒体 DNA 编码的 ETC 亚基表达之间的不同变化，这与其转录因子、核呼吸因子 1 和 2 以及共激活剂过氧化物酶体增殖物一致。活化受体 γ 共激活因子 1α。这些结果表明，在肌肉减少症中，HtrA2/Omi 蛋白酶活性的丧失通过对线粒体生物发生的差异调节来诱导线粒体核失衡。新的机制见解可能对开发新的肌肉减少症治疗策略很重要。