Abstract
Neurotrophic keratopathy (NK) is a degenerative corneal disease characterized by impaired corneal sensitivity and epithelial repair that is often linked to sensory nerve dysfunction. To establish a clinically relevant model and explore the mechanisms underlying NK pathogenesis, we developed a novel mouse model through partial transection of the ciliary nerve. This approach mimics the progressive nature of NK, reproducing key clinical features such as corneal epithelial defects, reduced sensitivity, diminished tear secretion, and delayed wound healing. Using this model, we investigated how disruptions in mitochondrial dynamics contribute to corneal epithelial dysfunction and impaired repair in NK. Our findings revealed substantial disruptions in mitochondrial dynamics, including reduced expression of fusion proteins (OPA1), downregulation of fission regulators (FIS1 and MFF), and impaired mitochondrial transport, as evidenced by decreased expression of Rhot1 and Kif5b. Additionally, the downregulation of mitophagy-related genes (Pink1 and Prkn) contributed to the accumulation of dysfunctional mitochondria, leading to DNA damage and impaired corneal epithelial repair. These mitochondrial abnormalities were accompanied by increased γH2AX staining, indicative of DNA double-strand breaks and cellular stress. This study highlights the pivotal role of mitochondrial dynamics in corneal epithelial health and repair, suggesting that therapeutic strategies aimed at restoring mitochondrial function, enhancing mitophagy, and mitigating oxidative stress may offer promising avenues for treating NK.