Ozone and PM2.5 co-exposure induced neurodegenerative alterations in mice: Implication of mitochondrial dysfunction in glial cells

Co-occurrence of ground-level ozone (O₃) and fine particulate matter (PM_2.5, ≤2.5 μm in aerodynamic diameter) has been a common air pollution scenario in urban areas worldwide. Existing evidence indicates exposure to O₃ or PM_2.5 is associated with neurodegenerative alterations. However, the association of co-exposure to O₃ and PM_2.5 with neurodegenerative disorders has been scarcely reported. This study examined neurodegenerative alterations following O₃ and PM_2.5 co-exposure and potential mechanisms. Ten-month-old male C57BL/6 mice were randomly divided into four groups: control, O₃, PM_2.5, and co-exposure (O₃ + PM_2.5). The conditions of co-exposure were established based on a real environmental exposure in the Central Plains Urban Agglomeration in Central China. Specifically, O₃ exposure was set at 0.6 ppm for 4 h/day over 30 consecutive days, while PM_2.5 exposure was performed through oropharyngeal aspiration of PM_2.5 suspension (5.6 mg/kg bw) every other day, 4 h prior to O₃ exposure. The results demonstrated that co-exposure significantly worsened memory impairment, neuroinflammation, blood–brain barrier (BBB) damage, and activation of glial cells, indicative of neurodegeneration. Omics approaches further revealed oxidative stress, mitochondrial injury, and endoplasmic reticulum stress in glial clusters following co-exposure. Moreover, strong associations between memory impairment, neuroinflammation, glial cell activation, and brain tissue damage with mitochondrial complex dysfunction in glial cells were uncovered. Taken together, O₃ and PM_2.5 co-exposure exacerbates neurodegenerative disorders, which involves mitochondrial complex dysfunction in glial cells, especially astrocytes. This study provides insights into the mechanisms underlying air pollution-induced neurodegenerative diseases.