Mitochondrial dysfunction elicits various stress responses in different model systems, but how these responses relate to each other and contribute to mitochondrial disease has remained unclear. Mitochondrial myopathy (MM) is the most common manifestation of adult-onset mitochondrial disease and shows a multifaceted tissue-specific stress response: (1) transcriptional response, including metabolic cytokines FGF21 and GDF15; (2) remodeling of one-carbon metabolism; and (3) mitochondrial unfolded protein response. We show that these processes are part of one integrated mitochondrial stress response (ISRmt), which is controlled by mTORC1 in muscle. mTORC1 inhibition by rapamycin downregulated all components of ISRmt, improved all MM hallmarks, and reversed the progression of even late-stage MM, without inducing mitochondrial biogenesis. Our evidence suggests that (1) chronic upregulation of anabolic pathways contributes to MM progression, (2) long-term induction of ISRmt is not protective for muscle, and (3) rapamycin treatment trials should be considered for adult-type MM with raised FGF21.

中文翻译：

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mTORC1调节线粒体综合应激反应和线粒体肌病进程。

线粒体功能障碍会在不同的模型系统中引发各种应激反应，但这些反应如何相互关联并导致线粒体疾病尚不清楚。线粒体肌病（MM）是成人发病的线粒体疾病的最常见表现，并表现出多方面的组织特异性应激反应：（1）转录反应，包括代谢性细胞因子FGF21和GDF15；（2）一碳代谢的重塑；（3）线粒体未折叠的蛋白质反应。我们显示这些过程是一个集成的线粒体应激反应（ISRmt）的一部分，线粒体应激反应受肌肉中mTORC1的控制。雷帕霉素对mTORC1的抑制下调了ISRmt的所有成分，改善了所有MM的特征，甚至逆转了晚期MM的进程，而没有引起线粒体的生物发生。