Our goals are to understand the process of mitochondrial biogenesis and our specific approach has been to focus on the biosynthesis of yeast mitochondrial tRNAs. An understanding of the structure, mechanisms and regulation of mitochondrial tRNA biosynthetic enzymes will be necessary to the goal of understanding mitochondrial biogenesis at the molecular level. Transfer RNA genes are transcribed into precursor RNA molecules and these precursors must be processed to yield mature tRNAs. The proteins necessary for the maturation events are coded by nuclear genes. We will isolate and characterize the nuclear components necessary to the maturation of mitochondrial tRNAs and clone the nuclear genes that code for them. One mitochondrial gene, other than the tRNA genes themselves, is essential for tRNA maturation. We have shown that this gene codes for an RNA subunit of the enzyme RNaseP. This enzyme removes 5' leaders from tRNA precursors. We will determine the primary and secondary structure of this RNA, define the requirements for the in vitro activity of the holoenzyme and its RNA subunit and elucidate the pathway of its biosynthesis. The expression of mitochondrial and nuclear genes necessary for tRNA biosynthesis will be examined under conditions known to perturb mitochondrial tRNA levels. The health relatedness of this project is several fold. First, mitochondria play a central role in cellular metabolism and mitochondrial derangements have been documented in neoplastic growth, heart disease and thyroid disease. An understanding of mitochondrial biogenesis may have far reaching implications that clearly transcend the rather basic research proposed here. Second, new insights on the complexity and diversity of the biological world have already been obtained from studying mitochondrial genes and future insights are promised in the work proposed here. Third, a combination of basic scientific investigations, coupled with more applied and clinical investigations, has increased our ability to make progress in solving biomedical problems.
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