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Deficiency of ?B crystallin augments ER stress-induced apoptosis by enhancing mitochondrial dysfunction.


ABSTRACT: 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 ?B crystallin as an important regulator of ER stress-induced cell death. Retinal pigment epithelial (RPE) cells from ?B crystallin (-/-) mice, and human RPE cells transfected with ?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 ?B crystallin, thus exacerbating mitochondrial dysfunction. Overexpression of ?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 ?B crystallin provides critical protection of mitochondrial function during ER stress-induced RPE apoptosis.

SUBMITTER: Dou G 

PROVIDER: S-EPMC3454510 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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

Dou Guorui G   Sreekumar Parameswaran G PG   Spee Christine C   He Shikun S   Ryan Stephen J SJ   Kannan Ram R   Hinton David R DR  

Free radical biology & medicine 20120708 5


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 αB crystallin as an important regulator of ER stress-induced cell death. Retinal pigment epithelial (RPE) cells from αB crystallin (-/-) mice, and human RPE cells transfected with αB crystallin siRNA, are more vulnerable to ER stress induced by  ...[more]

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