mTORC1 Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression

• Published in: Cell metabolism Vol. 26; no. 2; pp. 419 - 428.e5
• Main Authors: Khan, Nahid A., Nikkanen, Joni, Yatsuga, Shuichi, Jackson, Christopher, Wang, Liya, Pradhan, Swagat, Kivelä, Riikka, Pessia, Alberto, Velagapudi, Vidya, Suomalainen, Anu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2017
• Subjects: Animals; ATF4; Biochemistry and Molecular Biology; Biokemi och molekylärbiologi; Cell and Molecular Biology; Cell- och molekylärbiologi; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; folate cycle; Humans; integrated mitochondrial stress response; Male; Mechanistic Target of Rapamycin Complex 1 - genetics; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mice; Middle Aged; Mitochondria, Muscle - genetics; Mitochondria, Muscle - metabolism; Mitochondria, Muscle - pathology; mitochondrial disease; mitochondrial disease treatment; Mitochondrial Myopathies - genetics; Mitochondrial Myopathies - metabolism; Mitochondrial Myopathies - pathology; mitochondrial myopathy; nucleotide synthesis; one-carbon cycle; rapamycin; serine biosynthesis; Stress, Physiological; mitochondrial myopathy; serine biosynthesis; folate cycle; integrated mitochondrial stress response; mitochondrial disease treatment; one-carbon cycle; mitochondrial disease; rapamycin; ATF4; nucleotide synthesis
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2017.07.007

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. [Display omitted] •mtDNA replication defect activates mTORC1 and integrated mitochondrial stress response•mTORC1 upregulates mitochondrial 1C-cycle, FGF21, and UPRmt in mitochondrial disease•mTORC1 contributes to ragged-red fiber formation in mitochondrial myopathy•Rapamycin reverts progression of mitochondrial myopathy in mice Khan et al. report that mtDNA replication defect activates mTORC1, which drives an integrated mitochondrial stress response through ATF4 activation, inducing de novo nucleotide and serine synthesis, 1C-cycle, and FGF21 and GDF15 production. Downregulation of this response by rapamycin cured hallmarks of mitochondrial myopathy in mice.