Project summary Programmed cell death, phospholipid asymmetry, and paternal mitochondrial elimination are three vitally important, distinct, and interconnected biological processes essential for normal cell functions and animal development. Defects in these processes can cause various pathological conditions and human disease, including neurodegenerative disease, autoimmune disorders, various inherited human mitochondrial disease, and cancer. In this proposed work, we will carry out molecular genetic, reverse genetic, biochemical, cell biological, biophysical, and functional genomic analyses to decipher basic mechanisms of apoptosis, phospholipid asymmetry, and paternal mitochondrial elimination during animal development. For the study of apoptosis, we hope to understand the regulatory mechanisms and signaling pathways that control the release of mitochondrial apoptogenic factors during apoptosis and identify new targets and downstream pathways of the cell death protease that execute highly organized cell disassembly and rapid removal of the dying cells. For the study of phospholipid asymmetry, we plan to identify the molecular components and regulatory machineries that generate, maintain, and alter phospholipid asymmetry, decipher the functions and roles of specific phospholipids to a cell, and reveal the physiological and pathological consequences of altered phospholipid asymmetry to the cell and the animal. For the study of paternal mitochondrial elimination, we will investigate how and why paternal mitochondria are selectively recognized and targeted for elimination, the paternal and maternal factors and machineries required of this uniparental inheritance process, and the physiological significance of paternal mitochondrial elimination to embryo development and organismal fitness. These studies should reveal novel mechanisms, pathways, and genes that control these three fundamental biological processes, and ultimately, provide new targets, ideas, and strategies to facilitate treatment of numerous human diseases caused by abnormalities in these three important processes.