A Novel Strategy to Identify Substances that Improve Mitochnodrial Fitness

Project Summary Abstract Mitochondrial dysfunction causes mitochondrial diseases and is tightly linked to aging and neurodegenerative disorders such as Parkinsonandapos s and Alzheimerandapos s Recent discoveries support that mitochondrial dysfunction can be overcome to treat age related decline Cytegenandapos s hypothesis is that exercise induces the secretion of blood borne proteins that act systemically to stimulate removal of damaged mitochondria and enrichment of healthy mitochondria mitochondrial fitness The companyandapos s goal is to identify these proteins to develop into biologics that would serve as a platform to treat the myriad of diseases associated with mitochondrial dysfunction The discovery platform builds on existing work that exercise reversed mitochondrial dysfunction in a mouse model for mitochondrial disease Cells derived from the mutant mouse offer an attractive tool for identifying factors that improve mitochondrial fitness In this application the feasibility of a cell based assay platform is tested This platform measures colony formation mtDNA copy number mitochondrial respiration and expression of mitochondrial quality control proteins and will be evaluated in Aim using known agonists of mitochondrial biogenesis bezafibrate and the glitazones PPAR agonists metformin and AICAR AMPK and resveratrol Sirt The results will be integrated to develop a andquot fitness scoreandquot for each agonist Whether the assay platform is capable of rapidly differentiating agonistsandapos impact on mitochondrial biogenesis by their fitness score will be determined The utility of the assay platform for discovery of secreted factors will be evaluated in the second aim At least one factor identified by Cytegen to be significantly upregulated in exercised not sedentary mutant mice will be recombinantly produced and tested in the assay platform The fitness score will be compared to controls The completion of this work will identify to what extent the assay platform can be used for discovery purposes If successful this platform will help identify substances that enhance mitochondrial fitness that can be further pursued in a Phase II application for ultimate translation into clinical trials Project Narrative Mitochondrial dysfunction causes or contributes to many pathological conditions including cancer cardiomyopathies neurodegeneration aging and rare neuromuscular disorders This application proposes to evaluate exciting new technologies for discovering interventions that can restore mitochondrial function to successfully treat these diseases