Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis.
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Authors
Civiletto, Gabriele
Dogan, Sukru Anil
Cerutti, Raffaele
Fagiolari, Gigliola
Moggio, Maurizio
Lamperti, Costanza
Benincá, Cristiane
Publication Date
2018-11Journal Title
EMBO Mol Med
ISSN
1757-4676
Publisher
EMBO
Volume
10
Issue
11
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print
Metadata
Show full item recordCitation
Civiletto, G., Dogan, S. A., Cerutti, R., Fagiolari, G., Moggio, M., Lamperti, C., Benincá, C., et al. (2018). Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis.. EMBO Mol Med, 10 (11) https://doi.org/10.15252/emmm.201708799
Abstract
The mTOR inhibitor rapamycin ameliorates the clinical and biochemical phenotype of mouse, worm, and cellular models of mitochondrial disease, via an unclear mechanism. Here, we show that prolonged rapamycin treatment improved motor endurance, corrected morphological abnormalities of muscle, and increased cytochrome c oxidase (COX) activity of a muscle-specific Cox15 knockout mouse (Cox15 sm/sm ). Rapamycin treatment restored autophagic flux, which was impaired in naïve Cox15 sm/sm muscle, and reduced the number of damaged mitochondria, which accumulated in untreated Cox15 sm/sm mice. Conversely, rilmenidine, an mTORC1-independent autophagy inducer, was ineffective on the myopathic features of Cox15 sm/sm animals. This stark difference supports the idea that inhibition of mTORC1 by rapamycin has a key role in the improvement of the mitochondrial function in Cox15 sm/sm muscle. In contrast to rilmenidine, rapamycin treatment also activated lysosomal biogenesis in muscle. This effect was associated with increased nuclear localization of TFEB, a master regulator of lysosomal biogenesis, which is inhibited by mTORC1-dependent phosphorylation. We propose that the coordinated activation of autophagic flux and lysosomal biogenesis contribute to the effective clearance of dysfunctional mitochondria by rapamycin.
Keywords
Muscles, Lysosomes, Mitochondria, Animals, Mice, Inbred C57BL, Mice, Knockout, Mitochondrial Myopathies, Sirolimus, Electron Transport Complex IV, Motor Activity, Phenotype, Autophagy, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, TOR Serine-Threonine Kinases, Organelle Biogenesis, Rilmenidine
Sponsorship
European Research Council (322424)
Medical Research Council (MC_UP_1002/1)
Medical Research Council (MC_UU_00015/8)
MRC (MC_UU_00015/8)
Identifiers
External DOI: https://doi.org/10.15252/emmm.201708799
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287129
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