Identifying compounds that increase mitochondrial performance

The objective of this proposal is to isolate drugs that will enhance human physical and cognitive performance and resilience to trauma through enhancement of mitochondrial function. The significance of this opportunity is to reduce biological constraints on the modern army. Smaller, faster-moving fighting forces are constrained by physical endurance, which in turn is directly related to number and efficiency of muscle mitochondria. Additionally, mitochondrial function declines with age, contributing to the age-related loss of physical and cognitive performance. Experienced soldiers are forced to retire because of these losses of performance. Finally, field trauma leads to tissue death when metabolic reserves are insufficient. We have modified a high-throughput cell-based assay to sensitively monitor mitochondrial function, and will use this assay to screen for compounds increasing mitochondrial performance, through increased proliferation or increased electron transfer. We demonstrate that the assay detects a known mitoproliferation drug, and will optimize the assay for screening in 96 and 384-well plates in Phase I. In Phase II multiple drug and natural compound libraries will be screened, and mito-active drugs identified. The discovery of mitochondrial enhancers would represent an important step toward improving human performance and trauma resistance through augmentation of mitochondrial function througout aging.