Abstract
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.
Highlights
Mitochondrial diseases (MDs) represent a relevant group of inherited disorders with a cumulative prevalence of about 1:5,000 individuals (Gorman et al, 2015)
We provide a proof of principle for the genetic inactivation or downregulation of miR-181a/b exerting a protective effect from mitochondrial-mediated neurodegeneration in both in vitro and in vivo MD models, regardless of the underlying etiopathogenetic events highlighting these two miRNAs as potential, gene-independent, therapeutic targets for MDs characterized by neuronal degeneration
We found that miR-181a/b control genes implicated in mitochondrial biogenesis, functionality, and antioxidant response
Summary
Mitochondrial diseases (MDs) represent a relevant group of inherited disorders with a cumulative prevalence of about 1:5,000 individuals (Gorman et al, 2015). They are caused by mutations in either nuclear or mitochondrial genes resulting in oxidative phosphorylation (OXPHOS) impairment, leading to huge variability of symptoms, organ involvement, and clinical course. The clinical manifestations range from dysfunction of single tissue/structures such as the optic nerve in Leber’s hereditary optic neuropathy (LHON, MIM535000), to syndromic multi-organ conditions with a prominent involvement of the central nervous system (CNS), such as microphthalmia with linear skin lesions (MLS, MIM309801, 300887, 300952) and Leigh syndrome (LS, MIM256000).
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