Lipid-driven membrane remodeling engages a lysosome-dependent adaptive repair program during retinal aging

Abstract Age-associated remodeling of membrane lipid composition has been implicated in cellular dysfunction, yet the mechanisms linking lipid changes to membrane integrity and disease remain poorly defined. In the retinal pigment epithelium (RPE), lipid dysregulation is strongly associated with aging and age-related macular degeneration (AMD), a neurodegenerative disease of the central nervous system, but the causal pathways remain unclear. Here, we identify reduced activity of the lipid elongase ELOVL2 as a central driver of age-dependent membrane remodeling. Loss of ELOVL2-dependent polyunsaturated fatty acid (PUFA) elongation shifts plasma membrane lipid composition, leading to altered membrane biophysical properties and compromised membrane integrity. In response to this stress, RPE cells do not undergo apoptosis but instead activate a lysosome-dependent plasma membrane repair program that preserves barrier function under metabolic challenge. However, this adaptive response drives spatially polarized lysosomal exocytosis, promoting extracellular remodeling and accumulation of sub-RPE deposits associated with aging and AMD. Restoration of ELOVL2-derived lipid products reverses membrane abnormalities and suppresses lysosome-mediated remodeling phenotypes, demonstrating direct metabolic control of membrane homeostasis. Together, these findings define an ELOVL2-dependent lipid–lysosome axis that links PUFA elongation to plasma membrane integrity and reveals how compensatory repair mechanisms can contribute to tissue remodeling and disease progression in aging epithelia.