Loss of ELOVL2 triggers membrane repair in retinal cells
Loss of ELOVL2 triggers membrane repair in retinal cells
On August 29, Molecular Neurodegeneration published a study by Emily Thom and colleagues on the retinal pigment epithelium, the layer of cells behind the photoreceptors. Using cultured cells and mice, the authors traced a pathway from age-related lipid changes to membrane repair and tissue remodeling beneath this layer.
The retinal pigment epithelium supplies photoreceptors with nutrients and breaks down their spent components. Bruch's membrane lies between this epithelium and the blood vessels. Extracellular material accumulates at this interface with age. In samples of donor retinal pigment epithelium and in the retinas of old mice, the authors first identified signs of aging: expression changed in membrane-related genes, as did the abundance of long-chain polyunsaturated fatty acids.
They then examined ELOVL2, an enzyme that elongates these fatty acids. Reducing its activity in cells or disrupting it in mice lowered the abundance of these lipids and increased ceramide levels. The membrane became more ordered, with its lipids packed more tightly, while intracellular calcium levels rose. At the same time, lysosomes accumulated at the cell periphery and fused with the plasma membrane, releasing some of their contents outside the cell.
Lysosomes normally break down cellular material, but the authors propose that their movement to the cell surface in this setting helps repair the damaged membrane. In a cell layer whose apical and basal sides could be measured separately, more acid sphingomyelinase was released from the basal side toward Bruch's membrane. This enzyme converts one of the membrane lipids into ceramides. In mutant mice, APOE, a protein found in extracellular deposits, accumulated at the same interface. The authors therefore link sustained lysosomal membrane repair to remodeling of the extracellular environment beneath the retinal pigment epithelium.
The authors tested this pathway in the opposite direction by adding 24:5n-3, a direct product of ELOVL2. In a 2025 study, the same team showed that administering 24:5n-3 to old mice improved measures of visual function and reduced deposits beneath the retinal pigment epithelium. In the new study, adding 24:5n-3 to cells reduced signs of membrane stress and moved lysosomes away from the cell periphery. Intraocular administration to mice reduced ceramide accumulation and partially restored the structure of the retinal pigment epithelium. In the authors' model, a deficiency of ELOVL2 products changes membrane properties. Sustained lysosomal activity then preserves membrane integrity while also altering the tissue beneath the retinal pigment epithelium.