Drp1-driven fragmentation of scleral mitochondria promotes myopia development
Abstract
The global epidemic of myopia constitutes a growing public health concern worldwide. Myopia development is characterized by pathological scleral remodeling through fibroblast-myofibroblast transdifferentiation (FMT) and extracellular matrix (ECM) degradation. Since myopia is progressive, the development of sustainable and safe preventive interventions is imperative. While mitochondrial dynamics critically regulate fibrotic processes in other organs, their role in scleral homeostasis has remained unexplored. Here, we identify pathological mitochondrial fragmentation, caused by increased mitochondrial fission, as a key driver of myopia progression. Using two mammalian animal models, we demonstrate that both genetic and pharmacological enhancement of mitochondrial fission (inducing mitochondrial fragmentation) exacerbates collagen loss and accelerates axial elongation, whereas genetic and pharmacological inhibition of mitochondrial fission prevents collagen degradation and attenuates myopia progression. Hypoxia-induced FMT in cultured human scleral fibroblasts (HSFs) requires activation of mitochondrial fission, revealing overproduction of reactive oxygen species (ROS) as the downstream effector on HSFs and in both animal models. Our multilevel analyses identify the mitochondrial fission-ROS axis as a key pathway linking scleral hypoxia to ECM remodeling. Lycopene, a naturally occurring carotenoid antioxidant, significantly attenuated scleral ROS levels and was found suitable for long-term application, highlighting its potential as a therapeutic agent for myopia control. Collectively, these findings have identified a therapeutic target and agent for controlling myopia progression.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Zhenqi Guan
State Key Laboratory of Eye Health, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical University
Wenting Li
Shengcong Liu
State Key Laboratory of Eye Health, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical University
Xingxing Yang
Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering
Yuejia Peng
State Key Laboratory of Eye Health, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical University
Long Ye
School of Materials Science and Engineering, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Key Laboratory of Organic Integrated Circuits, Ministry of Education, Collaborative innovation Center of Chemical Science and Engineering (Tianjin)
Luyao Wang
Yuan Lu
Sisi Dong
State Key Laboratory of Eye Health, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical University
Huihui Liu
State Key Laboratory of Eye Health, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical University
Jian Yuan
Jianzhong Su
State Key Laboratory of Eye Health, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical University
Jia Qu
State Key Laboratory of Superhard Materials and Department of Physics
Xianqun Fan
Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine
Fei Zhao
Miaozhen Pan
State Key Laboratory of Eye Health, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical University
Xiangtian Zhou
State Key Laboratory of Eye Health, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical University