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

Mitochondrial diseases (MDs) are a heterogeneous group of devastating and often fatal disorders due to defective oxidative phosphorylation. Despite the recent advances in mitochondrial medicine, effective therapies are still not available for these conditions. Here, we demonstrate that the microRNAs miR‐181a and miR‐181b (miR‐181a/b) regulate key genes involved in mitochondrial biogenesis and function and that downregulation of these miRNAs enhances mitochondrial turnover in the retina through the coordinated activation of mitochondrial biogenesis and mitophagy. We thus tested the effect of miR‐181a/b inactivation in different animal models of MDs, such as microphthalmia with linear skin lesions and Leber's hereditary optic neuropathy. We found that miR‐181a/b downregulation strongly protects retinal neurons from cell death and significantly ameliorates the disease phenotype in all tested models. Altogether, our results demonstrate that miR‐181a/b regulate mitochondrial homeostasis and that these miRNAs may be effective gene‐independent therapeutic targets for MDs characterized by neuronal degeneration. Synopsis MicroRNAs 181a/b is important for mitochondria homeostasis in the retina. miR‐181a/b inactivation in different animal models of mitochondrial diseases protects neuronal degeneration and ameliorates the disease phenotype in tested models. miR‐181a/b control mitochondrial biogenesis in the retina and their downregulation enhances mitochondrial turnover through the coordinated activation of mitochondrial biogenesis and mitophagy. miR‐181a/b inhibition protects neurons from cell death and ameliorates the phenotype of different in vivo models of mitochondrial disease, i.e. such as Microphthalmia with Linear Skin Lesions (MLS) and Leber Hereditary Optic Neuropathy (LHON). miR‐181a/b may represent effective gene‐independent therapeutic targets for genetically heterogeneous mitochondrial diseases characterized by neuronal degeneration. Graphical Abstract MicroRNAs 181a/b is important for mitochondria homeostasis in the retina. miR‐181a/b inactivation in different animal models of mitochondrial diseases protects neuronal degeneration and ameliorates the disease phenotype in tested models.