mTORC1 Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression

Research output: Contribution to journalArticleScientificpeer-review

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.
Original languageEnglish
JournalCell Metabolism
Volume26
Issue number2
Pages (from-to)419–428
Number of pages10
ISSN1550-4131
DOIs
Publication statusPublished - 1 Aug 2017
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 1182 Biochemistry, cell and molecular biology
  • INTEGRATED MITOCHONDRIAL STRESS RESPONSE
  • ATF4
  • ONE-CARBON CYCLE
  • FOLATE CYCLE
  • SERINE BIOSYNTHESIS
  • NUCLEOTIDE SYNTHESIS
  • 3111 Biomedicine
  • MITOCHONDRIAL DISEASE
  • MITOCHONDRIAL DISEASE TREATMENT
  • RAPAMYCIN
  • MITOCHONDRIAL MYOPATHY

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