Mfn2 Regulates Scleral Remodeling in Myopia by Maintaining Endoplasmic Reticulum Homeostasis in Scleral Fibroblasts

Purpose: Endoplasmic reticulum (ER) stress participates in the development of various disorders by regulating tissue remodeling and apoptosis. This study aimed to explore the regulatory role of mitofusin 2 (Mfn2)-mediated ER stability in scleral remodeling in myopia. Methods: Myopia was induced in rats by form deprivation and hyperopic defocus. Scleral remodeling, ER stress, oxidative stress, and Mfn2 protein expression were examined in vivo. ER and mitochondrial ultrastructure were assessed by electron microscopy, and tissue apoptosis was evaluated. Primary rat scleral fibroblasts (SFs) were exposed to hypoxia to establish an in vitro myopia model, and Mfn2 expression in SFs was interfered by cell transfection. The extent of SFs transdifferentiation, extracellular-matrix remodeling, ER stress, mitochondrial damage, and cell apoptosis were assessed. Results: In this study, we discovered that tissue remodeling was accompanied by ER stress and oxidative stress in the sclera of myopic rats. Concomitantly, Mfn2 expression levels were significantly decreased, and the structures of the ER and mitochondria were damaged, along with tissue apoptosis. In vitro study showed that both hypoxia induction and MFN2 knockdown significantly increased hypoxia-inducible factor-1α expression in SFs. Mfn2 overexpression inhibited the transdifferentiation of hypoxia-induced SFs into myofibroblasts and upregulated the expression of collagen Iα1. Additionally, Mfn2 overexpression alleviated ER stress and mitochondrial damage in hypoxia-induced SFs, and reduced apoptosis of SFs. Conclusions: Our study revealed a critical role of Mfn2 in maintaining ER homeostasis in SFs, which conferred protective effects during scleral remodeling and provided a new therapeutic target for myopia.