Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis

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.

miR‐181a/b downregulation exerts a protective action on mitochondrial disease models

“…Current evidence supports the protective role of autophagy and mitophagy in MDs as well as in other neurodegenerative disorders associated with impairment of mitochondrial functions (Lightowlers et al , ; Viscomi et al , ; Civiletto et al , ). Since we showed that miR‐181a/b regulate mitophagy and autophagy in the eye, we tested whether the latter processes are implicated in the amelioration of the phenotype mediated by miR‐181a/b downregulation.…”

“…These data show that the downregulation of miR-181a/b ameliorates the phenotype in both MRC complex III and IV defective models, indicating that the protective effect of miR-181a/b silencing is gene-independent. Current evidence supports the protective role of autophagy and mitophagy in MDs as well as in other neurodegenerative disorders associated with impairment of mitochondrial functions (Lightowlers et al, 2015;Viscomi et al, 2015;Civiletto et al, 2018). Since we showed that miR-181a/b regulate mitophagy and autophagy in the eye, we tested whether the latter processes are implicated in the amelioration of the phenotype mediated by miR-181a/b downregulation.…”

“…Increased mitochondrial biogenesis and clearance were previously shown to exert protective effects in mitochondrial dysfunction (Viscomi et al, 2011;Johnson et al, 2013;Cerutti et al, 2014;Civiletto et al, 2015Civiletto et al, , 2018. We therefore decided to verify whether miR-181a/b inactivation could protect cells from mitochondrial damage.…”

“…MDs are biochemically and genetically heterogeneous, and their complexity has so far prevented the development of effective treatments (Sanchez et al , ). In the past few years, specific modulation of either mitochondrial biogenesis/dynamics or mitochondrial clearance/quality control has been tested as possible therapeutic strategies in different MD models (Viscomi et al , ; Johnson et al , ; Cerutti et al , ; Civiletto et al , , ). In spite of initial promising data, the latter approaches failed to be effective across different MD models [reviewed in Lightowlers et al (); Viscomi et al ()].…”

Mitochondrial Dynamics Regulation in Skin Fibroblasts from Mitochondrial Disease Patients

“…Preclinical studies suggest that a potential therapeutic target of disease progression is the mammalian target of rapamycin (mTOR) pathway, a biological route fundamental for regulating cell metabolism and physiology [13]. In mice models of Leigh syndrome, treatment with rapamycin, an mTOR inhibitor, extended lifespan and reduced disease progression and severity [14]. Civiletto et al provided evidence that rapamycin induces improvements in mitochondrial function and ultrastructure, indicating powerful clearance of dysfunctional organelles via activation of autophagic flux in skeletal muscle.Mitochondria are highly dynamic organelles that continuously fuse, divide, and move, and mitochondrial function is controlled and maintained by these morphologic changes.…”