Abstract
The primary underlying contributor for cataract, a leading cause of vision impairment and blindness worldwide, is oxidative stress. Oxidative stress triggers protein damage, cell apoptosis, and subsequent cataract formation. The nuclear factor-erythroid 2-related factor 2 (Nrf2) serves as a principal redox transcriptional factor in the lens, offering a line of defense against oxidative stress. In response to oxidative challenges, Nrf2 dissociates from its inhibitor, Kelch-like ECH-associated protein 1 (Keap1), moves to the nucleus, and binds to the antioxidant response element (ARE) to activate the Nrf2-dependent antioxidant system. In parallel, oxidative stress also induces endoplasmic reticulum stress (ERS). Reactive oxygen species (ROS), generated during oxidative stress, can directly damage proteins, causing them to misfold. Initially, the unfolded protein response (UPR) activates to mitigate excessive misfolded proteins. Yet, under persistent or severe stress, the failure to rectify protein misfolding leads to an accumulation of these aberrant proteins, pushing the UPR towards an apoptotic pathway, further contributing to cataractogenesis. Importantly, there is a dynamic interaction between the Nrf2 antioxidant system and the ERS/UPR mechanism in the lens. This interplay, where ERS/UPR can modulate Nrf2 expression and vice versa, holds potential therapeutic implications for cataract prevention and treatment. This review explores the intricate crosstalk between these systems, aiming to illuminate strategies for future advancements in cataract prevention and intervention.
Graphical Abstract
The Nrf2-dependent antioxidant system communicates and cross-talks with the ERS/UPR pathway. Both mechanisms are proposed to play pivotal roles in the onset of cataract formation.
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References
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Funding
This research was supported by the National Natural Science Foundation of China [grant number 82174474] (to Yan Liao); The National Eye Institute [R21EY033941] (to Hongli Wu); Department of Defense [W81XWH2010896] (to Hongli Wu); National Institutes of Health [R15GM123463-02] (to Kayla Green and Hongli Wu); National Institutes of Health [R25HL125447] (to Dr. J.K.Vishwanatha).
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XZ and BL conducted the literature search and drafted the manuscript. XZ prepares the illustration for the manuscript. HW, KL, HL, MT, XG, CE, MZ, TD, MLA, and EB helped revise the manuscript. HW and YL conceived the original idea and designed the outline of the study. All authors read and approved the final manuscript.
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Zhang, X., Liu, B., Lal, K. et al. Antioxidant System and Endoplasmic Reticulum Stress in Cataracts. Cell Mol Neurobiol 43, 4041–4058 (2023). https://doi.org/10.1007/s10571-023-01427-4
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DOI: https://doi.org/10.1007/s10571-023-01427-4