Mitochondrial shape and size are governed by frequent fission and fusion events. Recently, defects in mitochondrial morphological caused by aberrant mitochondrial fission and fusion in mitochondria have been found to lead to optic neurodegeneration associated with autosomal dominant optic atrophy (adOA), and in apoptosis. These findings underscore the physiological importance of mitochondrial fission and fusion in cells. We propose a chemical genetic approach to investigate both the molecular mechanisms and physiological implications of mitochondrial membrane dynamics. We have identified small molecule inhibitors of these processes through screens conducted at the Institute of Chemistry and Cell Biology at Harvard. The most potent to date is a mitochondrial fission inhibitor that targets the mitochondrial fission dynamin-related GTPase and acts with equal efficacy in yeast and mammalian cells. We will exploit this inhibitor to determine the mechanistic role of dynamin-related GTPases in mitochondrial fission. We will also characterize our other candidate inhibitors from our screen and identify their targets to examine the molecular mechanisms of both mitochondrial fission and fusion. We exploit our inhibitors further in mammalian cell culture model systems to examine the physiological role of mitochondrial membrane dynamics in apoptosis and to test the theraputic effects of small molecule fission inhibitors on optic atrophies that result from mitochondrial dysfunction.
