Early mitophagy defects and impaired mitochondrial energy metabolism drive target organ damage progression: Lessons from the Fabry heart

Increasing evidence supports a pathogenic role for impaired energy metabolism in organ damage. Genetic diseases provide opportunities to investigate these mechanisms, as exemplified by Fabry disease (FD), caused by an α-galactosidase A (GLA) deficiency and globotriaosylceramide (Gb3) accumulation, with cardiomyopathy as the leading cause of death. Beyond Gb3 storage, impaired energy metabolism may contribute to cardiomyopathy. Here, we demonstrate mitochondrial dysfunction in FD heart and its therapeutic targeting. Using a humanized FD mouse model (R301Q-Tg/GLA knockout), embryonic fibroblasts, and neonatal and adult cardiomyocytes, we found impaired mitophagy and mitochondrial respiration, increased reactive oxygen species, and a vicious cycle aggravating lysosomal dysfunction. These defects progressed with age, causing accumulation of dysfunctional mitochondria, energetic failure, apoptosis, cardiac hypertrophy, and diastolic dysfunction. L-arginine, promoting NO/PGC-1α-dependent mitochondrial rescue, prevented cardiac abnormalities. Our findings identify mitochondrial dysfunction as a key driver of FD cardiomyopathy and reveal the lysosome-mitochondria axis as a targetable pathway in FD and beyond.