Photoreceptors Clean Up Their Own Waste Inside the Retina

For decades, the prevailing view held that photoreceptors in the retina depended mainly on neighboring support cells—the retinal pigment epithelium (RPE)—to clear cellular waste. New findings from the University of Oklahoma challenge that view, showing that photoreceptors also carry out much of their own internal housekeeping. The study appears in Cell Death & Disease.

“Our study provides the first direct evidence that photoreceptors possess their own internal recycling system that is essential for their survival. Instead of relying solely on the RPE, photoreceptors recycle and break down their own damaged proteins and cellular components using lysosomes, the cell’s recycling centers,” said lead author Raju V.S. Rajala.

Each time people open their eyes, millions of photoreceptors convert light into signals the brain can interpret. Because these cells are constantly active and demand large amounts of energy, they continually generate damaged proteins and worn-out cellular parts that must be removed. Without an efficient recycling system, this waste accumulates, causing cells to malfunction and eventually die. 

To probe how this cleanup works, researchers removed an enzyme called PIKfyve in mice. Without it, the photoreceptors’ recycling system failed. Damaged proteins built up inside the cells, the photoreceptors gradually degenerated, and vision loss progressed over time.

The team also found that PIKfyve is critical for the health of the RPE itself. When the enzyme was absent, fats and cellular waste accumulated in these support cells, producing changes similar to those seen in age-related macular degeneration, a leading cause of vision loss in older adults.

“These discoveries change our understanding of retinal biology,” Rajala said. “Photoreceptors are not passive cells that depend entirely on the RPE for waste disposal. Instead, they possess an active quality-control system that continuously removes damaged proteins and maintains cellular health.”

The results may matter for many inherited retinal diseases, which are often tied to problems with cells’ ability to clear damaged proteins. By identifying PIKfyve as a central regulator of this process, the researchers highlight a potential target for therapies aimed at preserving vision before irreversible damage occurs.

The work also raises safety questions for drug development. A drug called Apilimod, which blocks PIKfyve, is under study as a potential treatment for autoimmune diseases, certain cancers, neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), and viral infections such as COVID-19 and Ebola. While the drug may help in those conditions, the new findings suggest that inhibiting PIKfyve could disrupt the retina’s natural recycling system, underscoring the need to carefully evaluate potential effects on vision during future clinical testing, Rajala said.