Deficiency of αB crystallin augments ER stress-induced apoptosis by enhancing mitochondrial dysfunction

Endoplasmic reticulum (ER) stress is linked to several pathological conditions including age-related macular degeneration. Excessive ER stress initiates cell death cascades which are mediated, in part, through mitochondria] dysfunction. Here, we identify alpha B crystallin as an important regulator of ER stress-induced cell death. Retinal pigment epithelial (RPE) cells from alpha B crystallin (-/-) mice, and human RPE cells transfected with alpha B crystallin siRNA, are more vulnerable to ER stress induced by tunicamycin. ER stress-mediated cell death is associated with increased levels of reactive oxygen species, depletion of glutathione in mitochondria, decreased superoxide dismutase activity, increased release of cytochrome c, and activation of caspases 3 and 4. The ER stress signaling inhibitors, salubrinal and 4-(2-aminoethyl) benzenesulfonyl fluoride, decrease mitochondrial damage and reduce RPE apoptosis induced by ER stress. Prolonged ER stress decreases levels of alpha B crystallin, thus exacerbating mitochondrial dysfunction. Overexpression of alpha B crystallin protects RPE cells from ER stress-induced apoptosis by attenuating increases in Bax, CHOP, mitochondrial permeability transition, and cleaved caspase 3. Thus, these data collectively demonstrate that alpha B crystallin provides critical protection of mitochondrial function during ER stress-induced RPE apoptosis. (C) 2012 Elsevier Inc. All rights reserved.