Deficiency of alphaB crystallin augments endoplasmic reticulum 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 mitochondrial dysfunction. Here, we identify alphaB crystallin as an important regulator of ER stress‐induced cell death. Retinal pigment epithelial (RPE) cells from alphaB crystallin (−/−) mice are more vulnerable to ER stress induced by tunicamycin. ER stress mediated cell death is associated with activation of caspase‐3 and caspase‐4, increased accumulation of reactive oxygen species and depletion of glutathione in mitochondria, increased release of cytochrome c from mitochondria, and translocation of Bcl‐2 family proteins. The ER stress signaling inhibitors, salubrinal and 4‐(2‐Aminoethyl) benzenesulfonyl fluoride, decrease mitochondrial damage and reduce RPE apoptosis induced by ER stress. Extensive ER stress decreases levels of alphaB crystallin. Overexpression of alphaB 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 alphaB crystallin constitutes a critical regulator of mitochondrial function during ER stress‐induced RPE apoptosis.