Cell-based High Throughput Screening of Compounds Improving Mitochondrial Energetics

Improving age-related decrease in cognitive and physical capabilities has tremendous potential for the civilian population and military personnel, including prolonged aptitude of highly-trained military personnel and lowering of healthcare costs. Mitochondria, the organelle responsible for energy production in eukaryotic cells, are directly involved in programmed cell death and associated to the aging process. Agave BioSystems and Professor Tom Fox at Cornell University propose to develop cell-based assays to monitor positive changes at the mitochondrial level. High throughput screening of compound collections will identify increases in mitochondrial mass or membrane potential in yeast cells and polynucleated myotybes. To develop an optimal screening strategy, assays will be developed with the yeast Saccharomyces cerevisiae and differentiated myotubes. Assays using yeast, with fast doubling time, should be more sensitive than mammalian cells. Myotubes will serve as a model system very close to post-mitotic tissues and allow detection of compounds that affect targets specific to mammalian cells. In addition to identifying new compounds, characterization of their mechanism of action will identify new targets, most likely in the nuclear genome or mitochondrial proteome, leading to development of focused target-specific screens as a means to identifying more potent and bioavailable compounds.