Suppressors of superoxide dismutase (SOD1) deficiency in Saccharomyces cerevisiae -: Identification of proteins predicted to mediate iron-sulfur cluster assembly

Yeast deficient in the cytosolic copper/zinc superoxide dismutase (SOD1) exhibit metabolic defects indicative of oxidative damage even under non-stress conditions, To help identify the endogenous sources of this oxidative damage, we isolated mutant strains of S. cerevisiae that suppressed metabolic defects associated with loss of SOD1. Six complementation groups were isolated and three of the corresponding genes have been identified. One sod1 Delta suppressor represents SSQ1 which encodes a hsp70-type molecular chaperone found in the mitochondria, A second sod1 Delta suppressor gene, designated JAC1, represents a new member of the 20-kDa J-protein family of co-chaperones, Jac1p contains a mitochondrial targeting consensus sequence and may serve as the partner for Ssq1p. Homologues of Ssq1p and Jac1p are found in bacteria in close association with genes proposed to be involved in iron-sulfur protein biosynthesis, The third suppressor gene identified was NFS1. Nfs1p is homologous to cysteine desulfurase enzymes that function in iron-sulfur cluster assembly and is also predicted to be mitochondrial. Each of the suppressor mutants identified exhibited diminished rates of respiratory oxygen consumption and was found to have reduced mitochondrial aconitase and succinate dehydrogenase activities. Taken together these results suggest a role for Ssq1p, Jac1p, and Nfs1p in assembly/maturation of mitochondrial iron-sulfur proteins and that one or more of the target Fe/S proteins contribute to oxidative damage in cells lacking copper/zinc SOD.