The long range goals of this proposal are to understand the process of mitochondrial and how this process may be regulated by developmental and physiological stimuli. As a necessary step in achieving these goals these studies will examine the biosynthesis of a mitochondrial complex of duel genetic origin to determine if the components of such a complex are coordinately expressed. The mitochondrial ribosome of S. cerevisiae is such a complex. The expression of nuclear-encoded mitochondrial ribosomal proteins will be examined to determine how their final steady-state levels are balanced with those ribosomal components that are coded in the mitochondria. An examination of the regulatory aspects of the biosynthesis of nuclear-encoded mitochondrial ribosomal proteins requires that probes be available to measure the expressioin of both mRNA and protein under conditions that perturb the synthesis of ribosomal components. To this end, mitochondrial ribosomal proteins will be purified and used both to isolate their corresponding genes and raise antibodies. Attempts will be made to overexpress these genes in yeast cells relative to other ribosomal components. If the steady- state levels of either mRNA coding for mitochondrial ribosomal proteins or the ribosomal proteins themselves cannot be substantially increased above that of other components, the mechanisms that regulate their expression to achieve balanced expression will be determined. Mitochondria play a central role in cellular metabolism and mitochondrial abnormalities and have been associated with many pathological conditions including certain neoplasms of the thyroid, parathyroid, and pituitary. More recent findings have suggested that lesions in the developmental regulation of mitochondrial biogenesis can lead to severe clinical disorders and death. As such, mitochondrial biogenesis and its regulation may be direct or contributing factors to many disease states. The combination of basic research such as that described within this proposal and clinical studies have been successfully used in the past for the therapeutic managements of diseases. It is anticipated that this combination will continue and may be used in the future to explore approaches to the therapeutic management of mitochondrial myopathies.
