Downregulation of two mitochondria-related miRNAs ameliorates the Leigh syndrome phenotype in Ndufs4 KO mice

Leigh syndrome (LS), also known as subacute necrotizing encephalomyelopathy, is one of the most frequent mitochondrial disorders affecting around 1 in 40,000 newborns. This condition is caused by mutations in over 115 genes, with mitochondrial respiratory chain complexes being the most affected. Early onset and rapid deterioration of cognitive and motor functions, leading to death within months or years, characterize the disease. Due to LS biochemical and genetic heterogeneity, effective treatments have not yet been developed. Gene/mutation-independent strategies are thus needed. We hypothesized that a synergic and fine-tuned modulation of pathways acting on mitochondrial homeostasis may ensure effective neuroprotection in mitochondrial disorders. In this respect, microRNA (miRNA) modulation is an attractive therapeutic strategy that has reached the preclinical and clinical stages. We demonstrated that miR-181a and miR-181b (miR-181a/b) regulate key genes involved in mitochondrial biogenesis and function and that their downregulation ameliorates the phenotype of different animal models of mitochondrial diseases [1]. Therefore, we decided to test if miR-181a/b downregulation may be exploited as a therapeutic strategy for LS using the Ndufs4 KO murine model. Our results show that genetic and Adeno Associated Viral (AAV) vector-mediated inactivation of miR-181a/b improves survival rate, ameliorates locomotor activity, and increases mitochondrial biogenesis. Based on the evidence above, we propose targeting miR-181a/b may represent a promising gene-independent therapeutic strategy for LS and other neurodegenerative disorders caused by mitochondrial dysfunction.