Summary: Researchers discovered that retinal photoreceptors manage their own internal waste disposal using lysosomes, overturning a decades-old belief that these lightsensing cells depended almost entirely on retinal pigment epithelium (RPE) support cells for waste removal.
The study demonstrates that photoreceptors possess a self-contained quality-control mechanism regulated by the enzyme PIKfyve. When researchers selectively removed PIKfyve in mouse models, damaged cellular proteins accumulated within photoreceptors, leading to progressive cell degeneration and vision loss.
In addition to triggering photoreceptor death, PIKfyve deficiency caused lipid and cellular waste accumulation in the RPE similar to pathology observed in age-related macular degeneration (AMD). The findings highlight PIKfyve as a key therapeutic target for inherited retinal diseases while raising safety warnings regarding systemic PIKfyve-inhibiting drugs currently in clinical trials.
Key Facts
- Autonomous Photoreceptor Recycling: Photoreceptors do not rely passively on the RPE for all waste processing; they actively break down and recycle their own damaged proteins and organelles using internal lysosomal pathways.
- Enzymatic Regulation via PIKfyve: The lipid kinase PIKfyve is the master enzymatic regulator controlling endolysosomal trafficking and waste degradation within photoreceptors and RPE support cells.
- Pathological Degeneration Model: Ablation of PIKfyve leads to massive waste buildup inside photoreceptor cell bodies, causing progressive retinal degeneration, cell loss, and permanent impairment of visual function.
- AMD-Like Retinal Pathology: Deletion of PIKfyve in RPE support cells causes accumulation of toxic fats and cellular waste, mimicking hallmark pathological features of age-related macular degeneration.
- Clinical Safety Warning: Apilimod, a PIKfyve-inhibiting drug candidate currently in development for autoimmune conditions, ALS, cancers, and viral infections, may pose unintended risks of retinal toxicity and visual degeneration.
Source: University of Oklahoma
For decades, scientists believed that photoreceptors in the retina relied primarily on neighboring support cells, known as the retinal pigment epithelium (RPE), to remove waste. While the RPE is still responsible for clearing away the worn-out tips of photoreceptors each day, new findings from the University of Oklahoma reveal that photoreceptors also perform much of their own internal housekeeping.
The study is published 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, Ph.D., an OU College of Medicine professor in the Dean McGee Department of Ophthalmology and Department of Biochemistry and Physiology.
Every time people open their eyes, millions of photoreceptors go to work converting light into signals the brain can interpret. Because these cells are constantly active and require tremendous amounts of energy, they continuously produce damaged proteins and worn-out cellular components that must be removed. Without an efficient recycling system, this cellular waste builds up, causing the cells to malfunction and eventually die.
To understand how this process works, researchers removed an enzyme called PIKfyve in mice. Without it, the photoreceptors’ recycling system broke down. Damaged proteins accumulated inside the cells and the photoreceptors gradually degenerated, leading to progressive vision loss.
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, one of the leading causes 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 findings may have important implications for many inherited retinal diseases, which are often linked to problems with cells’ ability to clear away damaged proteins. By identifying PIKfyve as a central regulator of this process, the researchers have uncovered a promising new target for therapies designed to preserve vision before irreversible damage occurs.
The research also raises important safety questions for drug development. A drug called Apilimod, which blocks PIKfyve, is currently being studied 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 prove beneficial for those conditions, the new findings suggest that inhibiting PIKfyve could interfere with the retina’s natural recycling system, highlighting the need to carefully evaluate potential effects on vision during future clinical testing, Rajala said.
Key Questions Answered:
A: For decades, vision science held that photoreceptors were largely dependent on the neighboring retinal pigment epithelium (RPE) layer to dispose of their cellular debris. This study shows that while RPE cells still engulf outer segment tips daily, photoreceptors maintain their own internal lysosomal recycling system to dispose of metabolic waste generated during high-energy phototransduction.
A: Without functional PIKfyve, the cell’s internal recycling pathway collapses. Damaged proteins accumulate inside photoreceptors, triggering cellular toxicity, progressive degradation, and photoreceptor cell death. Simultaneously, RPE cells accumulate toxic fats and debris, creating disease phenotypes characteristic of age-related macular degeneration (AMD).
A: Therapeutics like Apilimod deliberately inhibit PIKfyve to treat diseases such as ALS, viral infections, autoimmune conditions, and specific cancers. Because this study demonstrates that PIKfyve activity is essential for photoreceptor survival and RPE health, systemic administration of PIKfyve inhibitors carries a significant risk of causing off-target retinal toxicity and irreversible visual impairment.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this visual neuroscience research news
Author: April Wilkerson
Source: University of Oklahoma
Contact: April Wilkerson – University of Oklahoma
Image: The image is credited to Neuroscience News
Original Research: Open access.
“PIKfyve preserves endolysosomal function in photoreceptors and RPE cells to maintain retinal integrity” by Ammaji Rajala, Larissa J. Trevino, Thamaraiselvi Saravanan, Tyler M. Black, Mohd A. Bhat, Tuan Ngo, Mark Eminhizer, Jianhai Du, Visvanathan Ramamurthy & Raju V. S. Rajala. Cell Death and Disease
DOI:10.1038/s41419-026-08855-2
Abstract
PIKfyve preserves endolysosomal function in photoreceptors and RPE cells to maintain retinal integrity
Photoreceptors rely on efficient clearance of outer segment material and mislocalized proteins to maintain cellular health and visual function. While retinal pigment epithelial (RPE) cells remove shed outer segment tips through daily phagocytosis, the mechanisms by which photoreceptors eliminate misfolded or mistargeted proteins are not well understood.
Here, we identify PIKfyve, a lipid kinase that synthesizes phosphatidylinositol 3,5-bisphosphate [PI(3,5)P₂], as a key regulator of degradative and metabolic pathways in the retina. PIKfyve is highly expressed in rod photoreceptors, and its selective deletion causes progressive retinal degeneration marked by vacuolation, increased lysosomal markers, loss of outer nuclear layer thickness, and decline of rod and cone function.
Partial or complete reduction of PIKfyve further accelerates degeneration in P23H rhodopsin mutant mice. In the RPE, PIKfyve deficiency disrupts phagocytosis and autophagy, leading to the accumulation of rhodopsin, lysosomal proteins, and lipid droplets, accompanied by metabolic imbalance.
These results demonstrate that PIKfyve is essential for maintaining photoreceptor and RPE integrity by supporting lysosomal function, protein turnover, and metabolic stability, and suggest that enhancing PIKfyve activity may offer therapeutic potential for retinal degenerative diseases.
This study is timely, as pharmacological inhibition of PIKfyve with apilimod—currently under clinical investigation for autoimmune, neurodegenerative, and infectious diseases—raises significant safety concerns, including lysosomal swelling, vacuolization, and impaired protein degradation, which could ultimately compromise retinal homeostasis and vision.
