Biochemical mechanism of erastin-induced ferroptotic cell death in neuronal cells
Ming‐Jie Hou, Pan Wang, Bao Ting Zhu
Abstract
Ferroptosis is a new form of non-apoptotic cell death closely associated with glutathione (GSH) peroxidase 4 inhibition and/or GSH depletion, resulting in accumulation of cellular iron and lipid peroxides. The exact mechanism by which GSH depletion causes accumulation of reactive oxygen species (ROS) and lipid-ROS and subsequent ferroptotic cell death in neuronal cells remains unclear. In the present study, using immortalized HT22 mouse hippocampal neuronal cells as a model, we show that nitric oxide (NO) accumulation via protein disulfide isomerase (PDI)-mediated neuronal nitric oxide synthase (nNOS) activation plays a critical role in chemically-induced ferroptosis. Mechanistically, we find that erastin-induced GSH depletion leads to activation of PDI, which then mediates ferroptosis by catalyzing nNOS dimerization, followed by accumulation of cellular NO, ROS and lipid-ROS, and ultimately ferroptotic cell death. Pharmacological inhibition of PDI’s enzymatic activity or selective PDI knockdown each can effectively abrogate erastin-induced ferroptosis in HT22 cells. The results of this study reveal an important role of PDI in mediating chemically-induced ferroptosis in a neuronal cell model, and PDI may serve as a potential drug target for protection against GSH depletion-associated ferroptotic neuronal cell death.