# Dynamin‐Related Protein 1‐Dependent Disruption of Mitochondrial Homeostasis Drives Blue Light‐Induced Epithelial‐Mesenchymal Transition in Retinal Aging

## TL;DR

Blue light exposure damages retinal cells by causing mitochondrial dysfunction and cell transformation, but this can be reversed by targeting a key protein called Drp1.

## Contribution

The study identifies Drp1-mediated mitochondrial fission as a driver of blue light-induced epithelial-mesenchymal transition in retinal aging.

## Key findings

- Blue light exposure causes excessive mitochondrial fission and dysfunction in retinal pigment epithelial cells.
- Pharmacological inhibition of Drp1 restores mitochondrial homeostasis and reverses epithelial-mesenchymal transition.
- Drp1 inhibition in a mouse model preserves retinal function and slows AMD-like progression.

## Abstract

Age‐related macular degeneration (AMD) stands as a leading cause of blindness in the elderly, yet the fundamental aging processes that underpin its pathogenesis remain incompletely defined. The dysfunction of retinal pigment epithelial (RPE) cells is a central event in AMD, a process that shares key hallmarks with broader cellular aging, particularly the progressive decline in mitochondrial function. In this study, we investigated how a common environmental stressor—blue light—triggers a key pathological transformation, epithelial‐mesenchymal transition (EMT), in RPE cells by specifically disrupting mitochondrial dynamics, a core pillar of cellular aging. Using an in vitro model of human RPE cells, we demonstrated that blue light exposure induces a marked shift in mitochondrial dynamics towards excessive fission. This imbalance directly resulted in mitochondrial dysfunction, elevated oxidative stress, and served as the critical driver for the initiation of EMT. Importantly, pharmacological inhibition of the mitochondrial fission GTPase Dynamin‐related protein 1 (Drp1) with Mdivi‐1 effectively restored mitochondrial network homeostasis, rescued mitochondrial function, and fully reversed the EMT phenotype. These findings were corroborated in a mouse model of blue light‐induced retinal damage, where Drp1 inhibition successfully preserved retinal light responses, mitigated structural degeneration, and slowed disease progression. Our study demonstrates that Drp1‐mediated excessive mitochondrial fission drives EMT in RPE cells under blue light, linking this mechanism to AMD progression. Consequently, targeting mitochondrial dynamics to maintain cellular homeostasis emerges as a promising and broadly applicable geroscience‐based strategy for mitigating age‐related tissue dysfunction.

Blue light causes retinal injury by inducing excessive mitochondrial fission and epithelial‐mesenchymal transition in retinal pigment epithelial cells. Therapeutic targeting of Drp1 rescues this damage, restoring mitochondrial homeostasis and retinal integrity.