Coenzyme Q and Aging in Caenorhabditis elegans

描述：（由申请人提供）秀丽隐杆线虫是一种线虫

DESCRIPTION: (provided by applicant) The nematode Caenorhabditis elegans is an excellent model for genetic studies of the aging process. Mutations in the clk-1 gene of C. elegans result in an extended life span, slowed development and sluggish behavior. CLK-l is a mitochondrial polypeptide with sequence and functional conservation from humans to fungi. The yeast homologue of CLK-l(Coq7p), is essential for the biosynthesis of ubiquinone (coenzyme Q, or CoQ). The nematode, rat and human homologs of clk-1/COQ7 all function to restore CoQ biosynthesis in the yeast coq7 null mutant. Our recent studies of the C. elegans clk-l mutants suggest that the slowed rates of aging, development and behavior are due to a biochemical defect in CoQ biosynthesis. In the absence of dietary CoQ, (normally provided to nematodes by a diet of CoQ-replete E. coli) the clk-l mutants display their true phenotype - growth arrest in early development and sterility when emerging from the dauer stage. The questions addressed in this proposal focus on the relationship between CoQ and aging in the nematode model. The nature of the defect in the CoQ biosynthetic pathway in the clk-l mutants will be defined. These studies will make use of metabolic radiolabeling and analysis of total lipid extracts for CoQ and CoQ-intermediates. C. elegans clk-1 mutants fed the CoQ-replete E. coli rely on and assimilate this dietary CoQ. The regulation of uptake and distribution of dietary CoQ is not understood in any system. C. elegans provides a model for the assimilation and metabolism of exogenous CoQ in higher organisms. A similar metabolism of exogenous CoQ exists in wild type nematodes. The effect of dietary CoQ supplementation on the development, adult behavior and life span will be evaluated in wild type nematodes, and in other cog mutants of C. elegans. These studies will determine the effect of the clk-l mutations on the biosynthesis of CoQ in the nematode system; a model that is ideal for evaluating the relationship between coenzyme Q and aging. It is also likely that these studies will indicate whether C. elegans can provide a metazoan model uniquely suited to address questions regarding Q uptake, metabolism and distribution.