Role of Mitochondrial Reactive Oxygen Species in Chemically-Induced Ferroptosis1

Ferroptosis is a form of iron-dependent regulated cell death which is different from apoptosis. Chemically-induced ferroptosis is characterized by an accumulation of lipid reactive oxygen species (ROS) in the cells. A number of earlier studies have suggested the involvement of mitochondrial ROS in ferroptosis, and the present study seeks to further investigate the role of mitochondrial ROS in the induction of chemically-induced ferroptotic cell death. We find that during erastin-induced, glutathione depletion-associated ferroptosis, mitochondrial ROS accumulation is an important late event, which likely is involved in the final execution of ferroptotic cell death. The mitochondrion-originated ROS is found to accumulate in large quantities inside the nuclei during the late phases of erastin-induced ferroptosis. Completion of the late-phase accumulation of mitochondrion-produced ROS inside the nucleus of a cell likely marks an irreversible point in the cell death process. Similarly, accumulation of large amounts of mitochondrion-produced ROS inside the nucleus is also observed in the late phases of RSL3-induced ferroptosis. The results of this study indicate that the mitochondrial ROS play an important role in the final steps of both erastin- and RSL3-induced ferroptotic cell death.