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Cell Metab. 2017 Aug 1;26(2):419-428.e5. doi: 10.1016/j.cmet.2017.07.007.

mTORC1 Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression.

Author information

1
Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
2
Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland; Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan.
3
Department of Anatomy, Physiology, and Biochemistry, Swedish University of Agricultural Sciences, 75007 Uppsala, Sweden.
4
Research Programs Unit, Translational Cancer Biology, University of Helsinki, 00290 Helsinki, Finland.
5
Metabolomics Unit, Institute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland.
6
Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland; Department of Neurology, Helsinki University Hospital, 00290 Helsinki, Finland; Neuroscience Center, University of Helsinki, 00790 Helsinki, Finland. Electronic address: anu.wartiovaara@helsinki.fi.

Abstract

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.

KEYWORDS:

ATF4; folate cycle; integrated mitochondrial stress response; mitochondrial disease; mitochondrial disease treatment; mitochondrial myopathy; nucleotide synthesis; one-carbon cycle; rapamycin; serine biosynthesis

PMID:
28768179
DOI:
10.1016/j.cmet.2017.07.007
[Indexed for MEDLINE]
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