Mitoquinone alleviates bleomycin-induced acute lung injury via inhibiting mitochondrial ROS-dependent pulmonary epithelial ferroptosis.

Abstract

Numerous studies demonstrated that bleomycin (BLM) caused acute lung injury (ALI). This study explored the role of mitochondrial reactive oxygen species (ROS) on BLM-induced ALI and pulmonary epithelial ferroptosis. Male C57BL/6J mice were intratracheally injected with BLM (3.0mg/kg). BEAS-2B cells, human bronchial epithelial cells, were cultured with BLM (10μg/ml). Pulmonary MDA and 4-HNE, two markers of lipid peroxidation, were elevated in BLM-exposed mice. Oxidized lipids were upregulated in BLM-exposed BEAS-2B cells. Ferroptosis-characteristic ultrastructure, mainly disappearance of mitochondrial bilayer membrane structure and cristae, was observed in BLM-exposed pulmonary epithelium. Ferrostatin-1, a specific inhibitor of ferroptosis, attenuated BLM-evoked pulmonary lipid peroxidation, ferroptosis-characteristic mitochondrial ultrastructure and pulmonary epithelial death. The in vitro experiments showed that mitochondrial membrane potentials (MMPs) were decreased and mitochondrial ROS were increased in BLM-exposed BEAS-2B cells. Mitoquinone (MitoQ), a mitochondria-targeted antioxidant, prevented BLM-induced MMP reduction and mitochondrial ROS elevation in BEAS-2B cells. The in vivo experiment found that MitoQ attenuated BLM-evoked GSH depletion and lipid peroxidation in mouse lungs. Moreover, MitoQ prevented BLM-induced ferroptosis-characteristic mitochondrial changes, pulmonary epithelial death and ALI. In conclusion, mitochondrial ROS are an initiator of BLM-induced pulmonary epithelial ferroptosis. Mitochondria-targeted antioxidants may be used as potential therapeutic agents for BLM-induced ALI.