In this study we will use the Drosophila eye to understand how metabolic stress caused by aberrant mitochondriaI function can affect proliferation. We have shown that mutations in nuclear genes that encode mitochondria! proteins show a block in the cell cycle. For one such mutation, tend, the cell cycle block is due to the activation of a specific pathway including AMPK and p53 leading to the down-regulation of Cyclin E. Although mutant cells show a remarkable reduction in intracellular ATP levels, they do not die, but differentiate and undergo normal morphogenesis. Preliminary data indicates that the mitochondrion affects the cell cycle in different ways, one through the downregulation of the cell cycle activator Cyclin E, while another through the upregulation of a cell cycle inhibitor Dacapo. In this proposal we intend to dissect the pathways that lead from the mitochondrion to the cell cycle. We will use genetic and cell culture studies to determine how Cyclin E is regulated in tend and Dacapo in pdsw. Additionally many more mutants showing a cell cycle defect were isolated in a genetic screen that we will further characterize to identify genes that link the mitochondrion with the cell cycle machinery. The phenomenon being investigated here is novel, and the Drosophila eye can provide important insights into normal mitochondrial function that is important for the well being of a eukaryotic cell. Furthermore, the work has long-term clinical relevance for tumor growth control and in the understanding of inherited diseases, including those of the eye, caused by mitochondrial dysfunction.
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