期刊
CELL METABOLISM
卷 26, 期 2, 页码 419-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2017.07.007
关键词
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资金
- United Mitochondrial Disease Foundation
- Jane and Aatos Erkko Foundation
- Sigrid Juselius Foundation
- Academy of Finland
- University of Helsinki
- European Research Council [ERC-AdG10-268955]
- Helsinki Biomedical Graduate School
- Swiss National Foundation
- Novartis Foundation for medical biological research
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.
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