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

Abstract

Mitochondrial diseases ( MD s) 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 micro RNA s miR‐181a and miR‐181b (miR‐181a/b) regulate key genes involved in mitochondrial biogenesis and function and that downregulation of these mi RNA s 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 MD s, 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 mi RNA s may be effective gene‐independent therapeutic targets for MD s characterized by neuronal degeneration.

The Pervasive Role of the miR-181 Family in Development, Neurodegeneration, and Cancer

“…Interestingly, this role is dose-dependent because the IPL phenotype observed in the double-morphant embryos (MO-miR-181a/b), presents similar onset and progression but is considerably stronger and more highly penetrant when compared to the single depletion of miR-181a and miR-181b [26]. In agreement with a dose-dependent effect and functional redundancy of miR-181 family members, the disruption of the miR-181a1/b1 cluster only did not cause abnormalities in retinal morphology nor alteration of retinal function in the mice [28]. These data on retinal tissues support the concept that the ablation of all members of a miRNA family is necessary to reveal the complete range of miRNA functions in animal models.…”

“…Protective effect of down-regulation in vivo [28] Focal cerebral ischemia Protective effect of down-regulation in vivo [38] miR-181 Family in Cancer *…”

“…The role of a miR-181 family member in the CNS is also exemplified when analyzing retinal development. miR-181a and miR-181b are expressed in the Inner Nuclear Layer and Ganglion Cell Layer of the vertebrate retina [26,115], and at very low levels in the Outer Nuclear Layer [28,116]. In vertebrate models, such as medaka fish, both miR-181a and miR-181b are expressed in differentiating amacrine and ganglion cells of the developing retina and in different regions of the CNS, including the pretectal and tectal areas, which are visual areas in vertebrates [26].…”

“…miRNAs show a variety of important physiological functions in the CNS and perturbations of their expression profiles or those of their target genes have been associated with pathological processes affecting this system, including neurodegeneration [118,119]. The miR-181 family is highly expressed in different regions of the CNS and a functional role for the miR-181 family in more specific neurological processes such as neurotrophin signaling pathway, axon guidance, immunity, and mitochondrial-related pathways is also emerging [12,26,28,35,120]. Moreover, the deregulation of miR-181 family members has been reported in patients and animal models of neurodegenerative disorders such as Alzheimer's Disease (AD) [11,[16][17][18][19][20][21], Parkinson's Disease (PD) [22,23], and multiple sclerosis [121,122].…”

“…This is particularly true for miR-181a and miR-181b (miR-181a/b) while miR-181c and miR-181d display a more widespread expression as also evident after analysis with the tool available at http://ngs.ym.edu.tw/ym500v2/knownmir.php. In the particular analysis of genetic animal models harboring a targeted deletion of the miR-181a/b-1 loci revealed that this cluster accounts for most of the expression of the mature miR-181a/b in the brain and retina [24,27,28].…”