Genetic Dissection of the Eukaryotic Lipoylation Pathway in Saccharomyces cerevisiae Laura P. Pietikäinen1), M. Tanvir Rahman1), J. Kalervo Hiltunen1), Carol L. Dieckmann2), Alexander J. Kastaniotis1 1)Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, PO Box 5400, Oulu FI-90014, Finland. 2)Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA Mitochondrial fatty acid synthesis (mtFAS) is a highly conserved process in eukaryotes and required for the maintenance of respiratory competent mitochondria, respiratory complex integrity and properly functioning mitochondrial protein synthesis. We and others have suggested previously that mtFAS acts as an intramitochondrial mechanism for the sensing of cellular metabolic state, coordinating mitochondrial gene expression according to acetyl-CoA availability. Defects in mtFAS lead to neurodegenerative disease in humans. Octanoic acid is a well-documented product of mtFAS, serving as a precursor for the synthesis of the mitochondrial enzyme cofactor lipoic acid. If mtFAS defects can be alleviated by supplementation of appropriate metabolites is a pressing question. We have shown that mitochondrial mislocalization of the peroxisomal fatty acyl CoA ligase Faa2/Fam1 (FAM1-1 allele) rescues the respiratory deficient phenotype of all yeast mutants defective for mtFAS enzyme function as well as respiratory chain integrity, but not lipoylation. Our findings have important implications for the development of effective therapies for the treatment of LA or mtFAS deficiency-related disorders.