Molecular mechanisms of ferroptosis induction throughout germline development and aging

Project Summary/Abstract Molecular mechanisms of ferroptosis induction throughout germline development and aging Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation. Ferroptotic cell death is a component of human diseases, such as neurodegeneration, lung, and kidney disease. Promotion of ferroptosis may be a useful therapeutic to target cancerous tumors. Many unanswered questions surround this relatively newly discovered form of cell death, including the nature of lipid-mediator instigators of ferroptosis, how dietary components affect ferroptosis, and how metabolic processes involving cellular organelles such as mitochondria, ER, and cellular vesicles influence ferroptosis sensitivity. Furthermore, there is a dearth of studies examining whether ferroptosis affects germ cells and influences reproduction. We have developed a highly novel ferroptosis model using the small roundworm Caenorhabditis elegans. Our studies center on the induction of ferroptosis by dietary polyunsaturated fatty acids, which we have shown to specifically induce cell death in germ cells in young C. elegans. The powerful genetic tools in this model have allowed us to make rapid progress in the identification of modulators of diet-induced ferroptosis, especially in relation to lipid metabolism pathways, iron, and antioxidant protection. Importantly, our discoveries have been confirmed in mammalian models, including the important finding that ferroptotic cell death can be induced in cancer cell lines by addition of the polyunsaturated fatty acid dihomo-γ-linolenic acid (DGLA). We propose a multifaceted approach to discover and characterize molecular mechanisms of ferroptosis induction using genetic, dietary, and biochemical approaches. Furthermore, we will expand our studies of ferroptosis in germ cells to older worms to determine the role of ferroptosis in reproductive aging. Our experience and expertise, together with the flexible MIRA mechanism to pursue new research opportunities as they arise, will propel sustained progress. These studies will provide insights into the complex regulation of ferroptosis throughout development in a multicellular, living animal. Our findings may also contribute to novel cancer treatments or provide potential therapeutic targets for treatments of diseases promoted by ferroptosis.