Mitochondria are the main sites of cellular energy production in eukaryotes. Most mitochondrial proteins are encoded by nuclear genes, translated in the cytosol, and subsequently imported into mitochondria, while a few are encoded by mitochondrial DNA (mtDNA). Thus, mitochondrial function is controlled by both nuclear and mitochondrial genomes. In humans, mtDNA encodes 13 of the proteins involved in respiration. The mRNAs for these proteins are derived by processing of polycistronic primary transcripts that also contain mt rRNAs and tRNAs. The importance of mitochondrial gene expression to human well-being is underscored by the growing number of diseases that are being found to result from defects in mitochondrial gene expression in general, and from mitochondrial RNA processing in particular. Very little is known about the trans-acting factors that participate in this processing and in the subsequent function of the RNA. In order to understand in detail mitochondrial gene expression and its regulation in vertebrates, many fundamental questions still need to be addressed regarding the factors involved in mitochondrial RNA metabolism, beginning with studying in detail their identity and fundamental properties. The research proposed here aims at filling this gap by studying in detail the proteins that associate with mitochondrial RNA. The proposed work uses as a starting point the characterization of LRP130, which was recently identified as the most prominent protein among those that are crosslinked to mitochondria by UV irradiation of living cells. Mutations in LRP130 were recently found to cause (mitochondrial) cytochrome c oxidase deficiency in humans, in agreement with a potential direct role of LRP130 in mitochondrial RNA metabolism. Significantly, LRP130 has no recognizable RNA-binding domains. Our hypothesis is that LRP130 binds mRNA through a novel type of RNA-binding domain, that it is a major component of mitochondrial RNP complexes, and that it participates in the metabolism of mitochondrial RNA. This hypothesis will be tested by characterizing the RNA-binding activity of LRP130 and its associated proteins, by delineating in detail the composition of mitochondrial RNA-protein complexes in which LRP130 is found, and by beginning to investigate the function of LRP130 and its associated proteins in mitochondrial gene expression.
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