Norepinephrine Attenuates Benzalkonium Chloride-Induced Dry Eye Disease by Regulating the PINK1/Parkin Mitophagy Pathway

BackgroundIncreased reactive oxygen species (ROS) are involved in the pathological process of dry eye disease. Our previous results suggested that norepinephrine (NE) has a protective effect on dry eye.PurposeThis study explored the potential therapeutic role and underlying mechanisms of NE in benzalkonium chloride (BAC)-induced dry eye disease.MethodsBAC-pretreated human corneal epithelial cells (HCEpiC) were cultured with various concentrations of NE. A BAC-induced dry eye mice model was established to explore the role of NE. Alterations in mice corneal tissues, ROS levels, mitochondrial function, and mitophagy levels were analyzed.ResultsIn vitro, our results revealed that BAC-exposed HCEpiC led to mitochondrial malfunction, which involved excessive ROS production, decreased mitochondrial membrane potential (MMP), and promoted mitochondrial fragmentation through increased DRP1 and fission protein 1 (Fis1) expression and reduced mitofusin 2 (Mfn2) expression. Moreover, topical BAC application induced excessive mitophagy. These effects were reversed by NE. Additionally, the increased expression of LC3B, SQSTM1/p62, PINK1, and Parkin, which control mitophagy, in BAC-exposed HCEpiC was suppressed by NE. In BAC-induced C57BL/6J mice, NE resulted in lower fluorescein staining scores, decreased TUNEL-positive cells, and decreased mitochondrial fragmentation.ConclusionsIn conclusion, our findings showed that NE therapy prevented HCEpiC following BAC application by regulating mitochondrial quality control, which is controlled by PINK1/Parkin-dependent mitophagy. Our research suggests a potential targeted treatment for dry eye disease.