Mitochondria are essential, complex organelles of eucaryotic organisms required for a variety of metabolic processes including the generation of energy by oxidative phosphorylation. Biogenesis and maintenance of mitochondria requires the function of molecular chaperones such as Hsp7O. Our long term goal is to understand the mechanism of action of molecular chaperones within mitochondria using S. cerevisiae as a model system. Using genetic and biochemical approaches the analysis of the roles of mitochondrial chaperones of the Hsp7O and Hsp4O classes in the processes of protein translocation, folding and assembly of mitochondrial proteins will be continued. These studies are relevant to issues of human health, as certain human tissues, such as brain, heart, muscle and kidney, are particularly dependent on efficient mitochondrial function. Pathological effects caused by reduced bioenergetic capacity have been found to be caused by mutations in both mitochondrial and human DNA in human populations. In addition, one of the mitochondrial Hsp7Os has been implicated in the maturation of the homologue of human frataxin, which is associated with the neurodegenerative disease Freidrich's ataxia. Ssc1, an Hsp7O of the mitochondrial matrix, is an essential component of the apparatus required for translocation of proteins from the cytosol. Ssc 1 is tethered to the import channel via its interaction with an essential peripheral component of the channel, Tim44. Mge 1, an essential nucleotide release factor for Ssc 1, is also associated with Ssc1 at the import channel. Ssc1, an Hsp4O Mdjl, and the nucleotide exchange factor Mgel are thought to facilitate folding of imported proteins. This proposal is designed to understand the pathway of Ssc1 function in translocation of proteins across the mitochondnal proteins and their subsequent folding in the matrix. Ssq1 and Jaci are additional Hsp7Os and Hsp4Os, respectively, of the mitochondrial matrix. A role for Ssq1 in the regulation of iron metabolism and/or the assembly of Fe-S centers is indicated. Our goal is to understand the function(s) of Ssq1 in mitochondria and to provide insight into the cellular process(es) in which Ssql acts. The primary and secondary effects of the lack of Ssql function, focusing on iron metabolism, including its role in the maturation of Yfh 1, the yeast homologue of frataxin, and assembly of Fe-S clusters will be determined using a combination of genetic and biochemical techniques.
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