# Ambient light alleviates retinal neurodegeneration in mice by powering mitochondria via the engineered optoenergetic rhodopsin

## TL;DR

A new light-sensitive protein helps protect mouse retinal cells from degeneration by boosting energy production and reducing stress.

## Contribution

Engineered a mitochondria-targeting rhodopsin that uses ambient light to enhance ATP and reduce ROS in retinal cells.

## Key findings

- mt-EcGAPR increases ATP production and reduces ROS in retinal cells under stress.
- Ambient light activation of mt-EcGAPR protects retinal ganglion cells from degeneration in a glaucoma model.
- mt-EcGAPR inhibits ER stress and pyroptosis, preserving retinal structure and function.

## Abstract

The mitochondrial proton motive force (pmf) is a critical driver of cellular energy production and influences various cellular processes. Dysregulation of pmf is implicated in a range of diseases, including neurodegenerative diseases, mitochondrial diseases, cancer and aging-related pathologies. Currently, an efficient strategy to rescue ATP production and mitigate reactive oxygen species (ROS) generation under conditions of energy deprivation is lacking. Here, we engineered a light-sensitive, mitochondria-targeting proton-pumping rhodopsin (PPR), mt-EcGAPR, capable of generating an efficient pmf for ATP synthesis while simultaneously mitigating reactive oxygen species (ROS) generation during stress and decreasing DNA double-strand breaks (DSBs). Owing to its transparency to visible light, eye is the ideal candidate for the noninvasive application of mt-EcGAPR in the treatment of mitochondria-related retinal degenerative diseases. Using a silicone oil-induced ocular hypertension glaucoma mouse model, we demonstrate that ambient light activation of mt-EcGAPR significantly increased ATP production, suppressed ROS accumulation, and protected retinal ganglion cells (RGCs) from degeneration. Mechanistically, mt-EcGAPR inhibited endoplasmic reticulum (ER) stress-ATF6-gasdermin D (GSDMD)-mediated pyroptosis, thereby preserving retinal structure and function. This intervention ultimately led to improved visual acuity in glaucomatous eyes of mice. Collectively, our findings establish mt-EcGAPR as a promising therapeutic strategy for glaucoma and potentially other neurodegenerative diseases associated with mitochondrial dysfunction and impaired bioenergetics.