2. Academic Validation
  3. Age-Driven Lipid Remodeling Activates Lysosome-Mediated Plasma Membrane Repair

Age-Driven Lipid Remodeling Activates Lysosome-Mediated Plasma Membrane Repair

  • Res Sq. 2026 Jan 20:rs.3.rs-8607320. doi: 10.21203/rs.3.rs-8607320/v1.
Emily Tom 1 2,  Fangyuan Gao 2,  Carolina N Franco 3,  Adrian Wong 4,  Nathan Kemmerer 5,  Zichen Wang 4 6,  Qianlan Xu 1,  Yinyin Zhuang 7,  Samuel W Du 1 2,  Grazyna Palczewska 2,  Krzysztof Palczewski 1 2 8 9,  Itay Budin 4,  Xiaoyu Shi 7 8 10,  Vera L Bonilha 11 12,  Johannes Schöeneberg 4 6,  Karl J Wahlin 5,  Lauren V Albrecht 3 7,  Dorota Skowronska-Krawczyk 1 2
Affiliations

Affiliations

  • 1 Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, Irvine, CA.
  • 2 Gavin Herbert Eye Institute - Brunson Center for Translational Vision Research, Department of Ophthalmology and Visual Sciences, University of California, Irvine, Irvine, CA.
  • 3 Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California, Irvine, Irvine, CA.
  • 4 Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA.
  • 5 Shiley Eye Institute, University of California, San Diego, La Jolla, CA.
  • 6 Department of Pharmacology, University of California San Diego, La Jolla, CA.
  • 7 Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA.
  • 8 Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA.
  • 9 Department of Chemistry, University of California, Irvine, Irvine, CA.
  • 10 Department of Biomedical Engineering, University of California, Irvine, Irvine, CA.
  • 11 Department of Ophthalmic Research, Cleveland Clinic, Cleveland, OH.
  • 12 Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH.
PMID: 41646411 DOI: 10.21203/rs.3.rs-8607320/v1
Abstract

The abundance and stoichiometry of membrane lipid species vary across a cell's lifespan and metabolic state. In the retinal pigment epithelium (RPE), age-related alterations in lipid composition contribute to vision loss and diseases such as age-related macular degeneration (AMD), yet the molecular drivers of these changes remain unclear. Here, we show that age-dependent remodeling of the composition and biophysical properties of the plasma membrane compromises membrane integrity and function. Remarkably, rather than undergoing cell death, affected cells activate a lysosome-dependent plasma membrane repair program to preserve barrier integrity. While this adaptive response may protect RPE structure under metabolic stress, it also drives spatially polarized release of lysosomal contents that potentially can contribute to extracellular matrix remodeling and sub-RPE deposit formation during aging and AMD. Finally, we demonstrate that supplementation with the direct product of the aging-associated lipid elongase ELOVL2 alleviates these phenotypes, providing direct evidence for a critical role of ELOVL2-mediated PUFA elongation in healthy aging. Taken together, our results propose a model in which age-dependent decline in PUFA elongation disrupts the balance between membrane flexibility and stability, initiating a compensatory cycle of membrane stress and repair.

Keywords

aging; lysosomes; plasma membrane repair.

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