Difference between revisions of "Civiletto 2018 EMBO Mol Med"
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{{Publication | {{Publication | ||
|title=Civiletto G, Dogan SA, Cerutti R, Fagiolari G, Moggio M, Lamperti C, Benincá C, Viscomi C, Zeviani M (2018) Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis. EMBO Mol Med | |title=Civiletto G, Dogan SA, Cerutti R, Fagiolari G, Moggio M, Lamperti C, Benincá C, Viscomi C, Zeviani M (2018) Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis. EMBO Mol Med 10:e8799. | ||
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30309855 PMID: 30309855 Open Access] | |info=[https://www.ncbi.nlm.nih.gov/pubmed/30309855 PMID: 30309855 Open Access] | ||
|authors=Civiletto G, Dogan SA, Cerutti R, Fagiolari G, Moggio M, Lamperti C, Beninca C, Viscomi C, Zeviani M | |authors=Civiletto G, Dogan SA, Cerutti R, Fagiolari G, Moggio M, Lamperti C, Beninca C, Viscomi C, Zeviani M | ||
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|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<sup>sm/sm</sup>). Rapamycin treatment restored autophagic flux, which was impaired in naïve Cox15<sup>sm/sm</sup> muscle, and reduced the number of damaged mitochondria, which accumulated in untreated Cox15<sup>sm/sm</sup> mice. Conversely, rilmenidine, an mTORC1-independent autophagy inducer, was ineffective on the myopathic features of Cox15<sup>sm/sm</sup> 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<sup>sm/sm</sup> 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. | |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<sup>sm/sm</sup>). Rapamycin treatment restored autophagic flux, which was impaired in naïve Cox15<sup>sm/sm</sup> muscle, and reduced the number of damaged mitochondria, which accumulated in untreated Cox15<sup>sm/sm</sup> mice. Conversely, rilmenidine, an mTORC1-independent autophagy inducer, was ineffective on the myopathic features of Cox15<sup>sm/sm</sup> 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<sup>sm/sm</sup> 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=Autophagy, Lysosomal biogenesis, mTORC1, Mitochondrial disease, Rapamycin | |keywords=Autophagy, Lysosomal biogenesis, mTORC1, Mitochondrial disease, Rapamycin | ||
|editor=[[Plangger M]], | |editor=[[Plangger M]] | ||
|mipnetlab=IT Padova Viscomi C, TR Istanbul Dogan SA | |||
}} | }} | ||
{{Labeling | {{Labeling | ||
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|pathways=S, CIV | |pathways=S, CIV | ||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
|additional=Labels, 2018-10, | |additional=Labels, 2018-10, Rapamycin | ||
}} | }} | ||
Latest revision as of 14:46, 20 June 2023
| Civiletto G, Dogan SA, Cerutti R, Fagiolari G, Moggio M, Lamperti C, Benincá C, Viscomi C, Zeviani M (2018) Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis. EMBO Mol Med 10:e8799. |
Civiletto G, Dogan SA, Cerutti R, Fagiolari G, Moggio M, Lamperti C, Beninca C, Viscomi C, Zeviani M (2018) EMBO Mol Med
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 (Cox15sm/sm). Rapamycin treatment restored autophagic flux, which was impaired in naïve Cox15sm/sm muscle, and reduced the number of damaged mitochondria, which accumulated in untreated Cox15sm/sm mice. Conversely, rilmenidine, an mTORC1-independent autophagy inducer, was ineffective on the myopathic features of Cox15sm/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 Cox15sm/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: Autophagy, Lysosomal biogenesis, mTORC1, Mitochondrial disease, Rapamycin • Bioblast editor: Plangger M • O2k-Network Lab: IT Padova Viscomi C, TR Istanbul Dogan SA
Labels: MiParea: Respiration, Genetic knockout;overexpression, Pharmacology;toxicology
Pathology: Myopathy
Organism: Mouse Tissue;cell: Skeletal muscle Preparation: Isolated mitochondria
Coupling state: OXPHOS
Pathway: S, CIV
HRR: Oxygraph-2k
Labels, 2018-10, Rapamycin
