The identification of beneficial molecules for mitochondrial diseases: Saccharomyces cerevisiae as powerful model

Mitochondrial disorders (MD) are a group of rare clinically heterogeneous conditions, due to an impairment in the process of oxidative phosphorylation, responsible for the synthesis of ATP. MD may manifest at any age and in virtually any organ, although brain, skeletal muscle, liver and heart are most frequently involved because of their high-energy demand (mitochondrial encephalo-cardio-myopathies). Actually, for these diseases no proven effective therapies exist. For the current project, we have taken advantage of specific models of MD in Saccharomyces cerevisiae, previously characterized in our laboratory. The human pathological mutations studied are relative to the genes MPV17, ANT1, POLG, OPA1 and PANK2. The aim of the project is evaluating the effects of thousands of chemical substances in these yeast experimental models, to identify molecules with beneficial effects on specific MD or with a general positive influence on mitochondrial functioning. For this aim, we adopted an extensive genetic screening of drugs, called Drug Drop Test, in yeast models. All tested molecules are FDA approved so this approach of drug repurposing, makes faster the drug discovery process. The identified molecules were further characterized in yeast in order to better understand their impact on mitochondrial functionality. Some identified molecules have also shown beneficial effects in other model systems, including human cell lines. The confirmation of the positive preliminary data obtained in this study could lead to new pharmacological approaches for MD.