Exposure to diesel exhaust particles accelerated neuronal cell death in xenoferroptosis-susceptible cells

Air pollution is a public health concern and has amongst others been associated with the development or aggravation of neurodegenerative diseases. However, the underlying biological pathways remain poorly defined. Ferroptosis, a cell death dependent on lipid peroxidation, is associated with aging and the pathology of neurodegenerative diseases. In this study, we investigated whether exposure to particulate matter (PM)-diesel exhaust particles (DEP), biodiesel exhaust particles (BioDEP), and black carbon (BC)-could affect neuronal survival in conditions of increased vulnerability to ferroptotic cell death. Applying low PM concentrations up to 100 µg/mL to mouse hippocampal (HT22) neuronal cells did not induce substantial cell death. However, a combined exposure (or stimulation) of ferroptotic pathway inducers (glutamate, erastin, and RAS-selective lethal small molecule 3 (RSL3)) decreased neuronal cell survival with PM. As studied in detail for DEP, the combined challenge led to impaired cell metabolism, increased lipid peroxidation, calcium deregulation, mitochondrial reactive oxygen species (ROS) production and fragmentation, and led to xenoferroptotic cell death. Our findings suggest that PM in combination with a ferroptotic pathway inducer can accelerate neuronal cell death, increasing the pathology of neurodegenerative diseases in ferroptosis-susceptible cells.