“Mitochondria myopathies are genetic diseases characterized by impaired oxidative phosphorylation and caused by mutations in the mitochondrial or nuclear genome. We previously demonstrated that rapamycin, a well-known mTORC1 inhibitor, improved the motor performance and myopathic phenotype of a muscle-specific mouse model lacking Cox15 (Cox15sm), an enzyme involved in the biosynthesis of heme A. Mechanistically, rapamycin induced the nuclear translocation of transcription factor EB (TFEB), activating both lysosomal biogenesis and autophagy. However, since rapamycin has pleiotropic effects, including reduced protein translation and immune suppression, we investigated whether other TFEB activators could be beneficial in the Cox15sm mouse model. Urolithin A (UA) is a natural polyphenol produced by the microbiome by metabolizing ellagitannin and ellagic acid, two compounds abundant in pomegranate. UA has been reported to activate mitophagy, possibly by direct activation of TFEB.
We treated Cox15sm expressing the mitophagy reporter MitoQC with UA for 9 weeks by oral gavage starting at 30 days of age and monitored the motor performance by weekly treadmill test. Both treated and untreated Cox15sm mice had severely reduced running capacity at the beginning of treatment. However, UA-treated animals improved their motor performance from 30 to 200 m after 7 weeks of treatment. Morphological analysis of the skeletal muscle showed marked amelioration of the myopathy and robust induction of mitophagy, without increasing cytochrome c oxidase activity.
Our data support the idea that UA can be effective in ameliorating mitochondrial myopathies.”