Open AccessRapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis
Author(s) -
Civiletto Gabriele,
Dogan Sukru Anil,
Cerutti Raffaele,
Fagiolari Gigliola,
Moggio Maurizio,
Lamperti Costanza,
Benincá Cristiane,
Viscomi Carlo,
Zeviani Massimo
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201708799
Subject(s) - autophagy , mtorc1 , tfeb , mechanistic target of rapamycin , mitochondrial biogenesis , microbiology and biotechnology , mitochondrion , pi3k/akt/mtor pathway , biology , mitophagy , lysosome , mitochondrial myopathy , ulk1 , proteostasis , chemistry , phosphorylation , biochemistry , mitochondrial dna , signal transduction , ampk , protein kinase a , apoptosis , gene , enzyme
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 mTORC 1‐independent autophagy inducer, was ineffective on the myopathic features of Cox15 sm / sm animals. This stark difference supports the idea that inhibition of mTORC 1 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 mTORC 1‐dependent phosphorylation. We propose that the coordinated activation of autophagic flux and lysosomal biogenesis contribute to the effective clearance of dysfunctional mitochondria by rapamycin.