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Research article - Peer-reviewed, 2017

mTORC1 regulates mitochondrial integrated stress response and mitochondrial myopathy progression

Khan, Nahid A.; Nikkanen, Joni; Yatsuga, Shuichi; Jackson, Christopher; Wang, Liya; Pradhan, Swagat; Kivela, Riikka; Pessia, Alberto; Velagapudi, Vidya; Suomalainen, Anu

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.

Published in

Cell Metabolism
2017, Volume: 26, number: 2, pages: 419-428

    UKÄ Subject classification

    Cell and Molecular Biology
    Biochemistry and Molecular Biology

    Publication Identifiers

    DOI: https://doi.org/10.1016/j.cmet.2017.07.007

    Permanent link to this page (URI)

    https://res.slu.se/id/publ/86737