Rare, orphan mitochondrial diseases result from dysfunction of the mitochondria, organelles crucial for cellular metabolic processes. These complex diseases, which can be associated with pathogenic mutations in around 400 genes, occur at an incidence of 1 in 5000 in the overall population. The constellation of symptoms, tissues and cell types affected are variable and complex and despite advances in understanding the pathophysiology, the extremely varied phenotype–genotype relationship of MD has strongly limited the development of effective therapies. Presently there is no cure, only palliative therapies to relieve symptoms, highlighting the urgent need to establish platforms for the development of curative treatments for these debilitating diseases. In this MITOCURE program, we aim to validate our innovative 2-step approach to identify and develop novel MD therapeutics to correct, for the first time, the underlying mechanisms of mitochondrial dysfunctions.
In collaboration with the DARRI, our team has discovered a new, small-molecule hit that can improve mitochondrial function in wild type and mutant cell lines. This molecule, Mito12, which originated from a large-scale phenotypic screen of cells mutated for a mitochondrial disease gene, was subjected to SAR to identify a second-generation hit, which we term Mito89. We now wish to explore the alterations in cellular and mitochondrial gene expression (bulk RNAseq and proteomics) in treated and vehicle control (DMSO) cell lines to better understand the MoA.
