The recent finding of several homologues of the bacterial fatty acid synthesis pathway enzymes encoded by the mammalian nuclear genome has raised the possibility that mammalian cells contain two pathways to synthesize fatty acids: a mitochondrial bacteria-like pathway, and the textbook cytoplasmic pathway. The observation that this pathway is highly conserved from bacteria to mammals, and our finding that the expression of one or more components of the pathway is differentially regulated in a mouse model of mitochondrial disease, suggests that this pathway plays an important role in mitochondrial function. The first aim of the work proposed here is to show for the first time that mammalian mitochondria are capable of making fatty acids via this pathway. Chromatographic techniques will be used to identify the products and derivatives that are synthesized by the mitochondrial fatty acid synthesis (FASII) pathway. siRNA mediated knock-down of the pathway will be used to further elucidate the function of this pathway in the cell. The second specific aim of this proposal is to investigate the role of the mitochondrial FASII pathway in Alzheimer's disease. The proposed phenotypes that would be expected from inhibition of the FASII pathway resemble the mitochondrial dysfunction seen in the brain of patients with Alzheimer's disease. The possibility that B-amyloid causes mitochondrial dysfunction through inhibition of the fatty acid synthesis pathway will be investigated through incubation of mitochondria with B-amyloid, and analysis of the products of mitochondrial FASII. The discovery of an association between the mitochondrial FASII pathway and Alzheimer's disease may provide insight into and treatment options for Alzheimer's, Parkinson's, and other neurodegenerative disorders. [unreadable] [unreadable]