Mitochondrial dysfunction is a major cause of liver pathology by participating in oxidative stress and cell death. Mitochondria continually change their morphology and location inside the cell. Dynamic changes in mitochondrial morphology involve mainly fission and fusion of mitochondrial tubules. However, the functional significance of the dynamic behavior of mitochondria is not well understood. The mitochondrial electron transport chain (ETC) is the major source of reactive oxygen species (ROS) that contributes to oxidative stress conditions. Our studies have demonstrated that inhibiting mitochondrial fission decreases cellular ROS levels in ROS-overproducing conditions, which in turn reduces oxidative stress-induced cell death. Our long-term objectives are to elucidate molecular mechanisms of mitochondrial fission/fusion, and to define the physiological roles of mitochondrial dynamics. In this application, we will continue to study the molecular mechanisms of how mitochondrial fission and fusion proteins control mitochondrial morphology, and investigate the role of mitochondrial dynamics in mitochondrial activity and liver function. The central hypothesis of this proposal is that networks of molecular interactions involving fission and fusion proteins on the mitochondrial membrane regulate mitochondrial morphology and function, and play an integral role in health and pathology of the liver. In the first specific aim, we will study the molecular mechanisms that control the fission/fusion balance of mitochondria. In the second specific aim, we will investigate the involvement of the mitochondrial fission protein hFis1 in mitochondrial fission and apoptosis. The third specific aim is to understand the physiological significance of mitochondrial morphology by focusing on its relationship with the ETC activity and ROS generation in hepatocytes. We will also test whether mitochondrial fission can be a useful target to control liver injury using a cholestatic liver model how mitochondrial dynamics contribute to the regulation of mitochondrial function and cell physiology in health and diseases of the liver. PUBLIC HEALTH RELEVANCE: Growing evidence indicates that control of mitochondrial morphology is a fundamental cellular process determining cell life and death, and we believe that information from these studies will greatly increase our understanding of how mitochondrial dynamics contribute to the regulation of mitochondrial function and cell physiology in health and diseases of the liver.