Lipid and Cholesterol Peroxidation Leads to α-Crystallin Membrane Aggregation and Cataract Formation.

Purpose: The significant lens chaperone protein α-crystallin (αABc), comprised of αA-crystallin (αAc) and αB-crystallin (αBc) subunits, is found to form membrane-bound aggregates with age and cataract formation. However, the molecular basis for such aggregate formation is still unclear. Our research primarily aims to elucidate the effect of lipids (phospholipids and sphingolipids) and cholesterol (Chol) peroxidation on the aggregation of αAc, αBc, and αABc to bovine lens nuclear membrane (NM). Methods: Lipid and Chol peroxidation was induced by a photosensitized peroxidation reaction, and topographical images of NM and oxidized-NM (Ox-NM) with and without αAc, αBc, or αABc were obtained using atomic force microscopy (AFM). Results: The percentage of membrane area occupied (PMAO) by αAc, αBc, or αABc aggregates on NMs was significantly smaller without lipid and Chol peroxidation. However, with NM lipid and Chol peroxidation, the PMAO of αAc, αBc, or αABc aggregates on the Ox-NM was significantly more extensive, and PMAO increased with an increase in lipid and Chol peroxidation. Large-size aggregates of αAc, αBc, or αABc on Ox-NM with the depressed central region for αAc and αABc aggregates on Ox-NM were observed to a greater extent with increased lipid and Chol peroxidation. Conclusions: Lipid and Chol peroxidation induce membrane defects on NM, followed by extensive aggregation of αAc, αBc, and αABc on Ox-NM, suggests that lipid and Chol peroxidation promotes the aggregation of αAc, αBc, and αABc to Ox-NM, and the formation of such large aggregates likely promotes increased light scattering and cataract formation.