ER Stress and Apoptosis: A New Mechanism for Retinal Cell Death

Figure 2

ER stress-associated apoptotic pathways in retinal diseases. A variety of pathogenic factors in chronic retinal degenerative diseases (e.g., age-related macular degeneration, glaucomatous retinopathy and diabetic retinopathy), including aging, oxidative stress, hypoxia, inflammatory factors, and hyperglycemia and others, can disturb ER function and compromise the adaptive UPR, resulting in persistent ER stress in retinal cells. This leads to sustained activation of the ATF4/CHOP pathway and the IRE1/TRAF2/ASK/JNK pathway. Both JNK and CHOP attenuate the function of the pro-survival factor Bcl-2, but enhances the activity of proapoptotic Bcl-2 proteins such as Bim, Bax, and PUMA, resulting in mitochondrial dysfunction and cytochrome c release. In addition, caspase-12 is activated during ER stress, which sequentially activates caspase-7 and/or caspase-3, leading to mitochondria-independent apoptosis.