Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis. Issue 11 (11th October 2018)

• Record Type: Journal Article
• Authors: Civiletto, Gabriele; Dogan, Sukru Anil; Cerutti, Raffaele; Fagiolari, Gigliola; Moggio, Maurizio; Lamperti, Costanza; Benincá, Cristiane; Viscomi, Carlo; Zeviani, Massimo
• Is Part Of: EMBO molecular medicine. Volume 10:Issue 11(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-10-11
• Subjects: autophagy -- lysosomal biogenesis -- mitochondrial disease -- mTORC1 -- rapamycin; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201708799
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: Mitochondrial diseases are a large family of genetic disorders for which no cure is currently available. Rapamycin, a TORC1‐dependent autophagy activator, ameliorates the phenotype a muscle‐specific Cox15 sm/sm mouse model of severe mitochondrial myopathy. Rapamycin increases the reduced autophagic flux in the skeletal muscle of Cox15 sm/sm mice. Rilmenidine, a mTORC1‐independent autophagy inducer, increases autophagy without rescuing the phenotype of Cox15 sm/sm mice. By inhibiting mTORC1, rapamycin induces the translocation of TFEB to the nucleus, inducing lysosomal biogenesis. The coordinated activation of autophagy and lysosomal biogenesis contributes to the beneficial effects of rapamycin in Cox15 sm/sm mice. Abstract : Mitochondrial diseases are a large family of genetic disorders for which no cure is currently available. Rapamycin, a TORC1‐dependent autophagy activator, ameliorates the phenotype a muscle‐specific Cox15 sm/sm mouse model of severe mitochondrial myopathy.