7. Project Summary. Mitochondrial damage, and mitochondrial fatty acid synthase (mtFAS) disorders in particular, have been associated with aging and neurodegenerative disease. Historically these disorders were attributed to a decrease in lipoic acid production, however, this conclusion has recently come into question with the growing evidence that the mitochondrial acyl carrier protein (mtACP), the substrate-shuttling protein of mtFAS, plays a much greater role within mitochondrial metabolic pathways. A hierarchy of mtACP regulation, from mitochondrial protein translation to respiratory complex assembly, has been recently revealed, however the molecular basis of such control remains unclear. This program aims to apply new chemical, structural, and biophysical tools to understand how acyl-mtACP interacts within the mitochondrial metabolism. Given the central role of the mitochondria in cellular metabolism, this program will fundamentally impact our understanding of aging and health maintenance and provide potential new avenues to treatment of mitochondrial diseases.