Attenuation of PM2.5-induced alveolar epithelial cells and lung injury through regulation of mitochondrial fission and fusion

Background: Exposure to particulate matter (PM) with an aerodynamic diameter less than 2.5μm (PM 2.5 ) is a risk factor for developing pulmonary diseases and the worsening of ongoing disease. Mitochondrial fission and fusion are essential processes underlying mitochondrial homeostasis in health and disease. We examined the role of mitochondrial fission and fusion in PM 2.5 -induced alveolar epithelial cell damage and lung injury. Key genes in these processs include dystrophin-related protein 1 (DRP1) and optic atrophy 1 (OPA1) respectively. Methods: Alveolar epithelial (A549) cells were treated with PM 2.5 (32mg/ml) in the presence and absence of Mdivi-1 (10μM, a DRP1 inhibitor) or BGP-15 (10μM, an OPA1 activator). Results were validated using DRP1-knockdown (KD) and OPA1-overexpression (OE). Mice were injected intraperitoneally with Mdivi-1(20mg/kg), BGP-15 (20 mg/kg) or distilled water (control) one hour before intranasal instillation of PM 2.5 (7.8 mg/kg) or distilled water for two consecutive days. Results: PM 2.5 exposure of A549 cells caused oxidative stress, enhanced inflammation, necroptosis, mitophagy and mitochondrial dysfunction indicated by abnormal mitochondrial morphology, decreased mitochondrial membrane potential (ΔΨm), reduced mitochondrial respiration and disrupted mitochondrial fission and fusion. Regulating mitochondrial fission and fusion pharmacologically using Mdivi-1 and BGP-15 and genetically using DRP1 KD and OPA1 OE prevented PM 2.5 -induced celluar damage in A549 cells. Mdivi-1 and BRG-15 attenuated PM 2.5 -induced acute lung injury in mice. Conclusion: Increased mitochondrial fission and decreased mitochondrial fusion may underlie PM 2.5 -induced alveolar epithelial cell damage in vitro and lung injury in vivo. Regulation of mitochondrial fission and fusion may represent a useful future therapeutic strategy.