Rare mitochondrial neurodegenerative conditions

Microphthalmia with linear skin lesions (MLS) is an X-linked dominant male-lethal disorder associated with mutations in holocytochrome c-type synthase (HCCS), which encodes a crucial player of the mitochondrial respiratory chain (MRC). However, not all clinically diagnosed MLS cases have mutations in HCCS. This study identified COX7B, a poorly characterized structural subunit of cytochrome c oxidase (COX), as being responsible for some of these forms. Downregulation of COX7B in medaka resulted in microcephaly and microphthalmia that recapitulated the MLS phenotype and demonstrated an essential function in vertebrate Central Nervous System (CNS) development. Our laboratory is currently involved in the characterization of this model aiming at studying the role of HCCS in eye development and in mitochondrial functions and programmed cell death, and defining the pathogenetic mechanisms underlying microphtalmia with linear skin lesions (MLS) syndrome. Another field of study of our lab, are the mitochondrial diseases (MDs), 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. 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. The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from July 2016 until last budget year, calculated based on the size of the research group.