Mitochondrial microRNAs are dysregulated in patients with Fabry Disease.

Fabry disease (FD) is a lysosomal storage disorder caused by mutations in the gene for alpha- galactosidase A (GAL) inducing a progressive accumulation of globotriaosylceramide (Gb3) and its metabolites in different organs and tissues. GB3 deposition does not fully explain the clinical manifestations of FD, and other pathogenetic mechanisms have been proposed requiring the identification of new biomarkers for monitoring FD patients. Previous evidence suggests the involvement of mitochondrial alterations in FD. Here, we propose mitochondrial related microRNA (miRNAs, miRs) as potential biomarkers of mitochondrial involvement in FD. We observed that miRNAs regulating different aspects of mitochondrial homeostasis including expression and assembly of respiratory chain, mitogenesis, antioxidant capacity, and apoptosis are consistently dysregulated in FD patients. Our data unveil a novel non-coding RNA signature of FD patients, indicating mitochondrial related miRNAs (mitomiRs) as new potential pathogenic players and biomarkers in FD. Significance Statement We demonstrate for the first time that a specific signature of circulating mitochondrial microRNAs (mitomiRs) are dysregulated in Fabry disease (FD). In our study, we observed that mitomiRs regulating fundamental aspects of mitochondrial homeostasis, including expression and assembly of the respiratory chain, mitogenesis, antioxidant capacity, and apoptosis are significantly dysregulated in FD patients. Taken together, our new findings introduce mitomiRs as unprecedented biomarkers of FD and point at mitochondrial dysfunction as a novel potential mechanistic target for therapeutic approaches.