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

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.