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

  • Ocul Immunol Inflamm. 2024 Dec 27:1-15. doi: 10.1080/09273948.2024.2447816.
Han Zhao  1  2 ,  Wushuang Wang  3  4 ,  Yun Yang  3  4 ,  Changming Feng  3  4 ,  Tong Lin  3  4 ,  Lan Gong  3  4
Affiliations
  • 1. Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
  • 2. Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China.
  • 3. Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China.
  • 4. Laboratory of Myopia, NHC Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, Shanghai, China.
PMID: 39731302 DOI: 10.1080/09273948.2024.2447816
Abstract

Background: Increased 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.

Purpose: This study explored the potential therapeutic role and underlying mechanisms of NE in benzalkonium chloride (BAC)-induced dry eye disease.

Methods: BAC-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.

Results: In 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.

Conclusions: In 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.

Keywords
Benzalkonium chloride; dry eye disease; mitochondrial dysfunction; mitophagy; norepinephrine.
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