mTORC1 Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression

Publication date: 1 August 2017
Source:Cell Metabolism, Volume 26, Issue 2
Author(s): Nahid A. Khan, Joni Nikkanen, Shuichi Yatsuga, Christopher Jackson, Liya Wang, Swagat Pradhan, Riikka Kivelä, Alberto Pessia, Vidya Velagapudi, Anu Suomalainen
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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Teaser

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.


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