Upregulation of the Unfolded and Mitochondrial Unfolded Protein Responses in Oxidative Stress-Induced Cataract
- 1Chemical and Physical Biology Program, Vanderbilt University, Nashville, Tennessee 37212, United States.
- 2Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37212, United States.
- 3Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37232, United States.
Abstract
Purpose:: Oxidative stress is thought to contribute to the development of age-related cataracts (ARCs), but the mechanisms by which oxidative damage leads to the opacification of the lens remain unclear. Previous studies suggest that oxidative stress can disrupt lens proteostasis. Therefore, it was hypothesized that ARCs arise from proteomic changes driven by an age-associated decline in oxidative stress defenses that interact with the lens proteostatic state. To test this hypothesis, proteomic analyses of lenses exposed to oxidative stress were performed to examine oxidative and proteostatic stress responses in vivo.
Methods:: Cataract formation was induced by injecting hydrogen peroxide into the aqueous humor of adult zebrafish. nrf2fh318/fh318 zebrafish were used to model the reduced oxidative stress protection observed in aged human lenses, while cryaba−/− zebrafish were used to model impaired lens proteostasis. Resulting opacities in WT, cryaba−/−, nrf2fh318/fh318, and cryaba−/−; nrf2fh318/fh318 lenses were quantified and proteomic changes in the cortex were analyzed using data independent acquisition Parallel Accumulation Serial Fragmentation mass spectrometry.
Results:: Hydrogen peroxide treatment induced the formation of cortical cataracts. Proteomic results showed that, dependent on genotype and day, oxidative stress activates the unfolded and mitochondrial unfolded protein responses. Additional changes were also observed in energy metabolism, Ca2+ homeostasis, protein degradation, and cytoskeletal and extracellular matrix remodeling pathways.
Conclusions:: Treated zebrafish lenses successfully model ARC and mass spectrometry proteomics identified the unfolded and mitochondrial unfolded protein responses as potential therapeutic targets for ARC.
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BibTeX
@misc{zelle2026upregulation,
title = {{Upregulation of the Unfolded and Mitochondrial Unfolded Protein Responses in Oxidative Stress-Induced Cataract}},
author = {Sarah R. Zelle and W. Hayes McDonald and Hassane S. Mchaourab and Kevin L. Schey},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.19.745850},
url = {https://europepmc.org/article/PMC/PMC13722104},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Upregulation of the Unfolded and Mitochondrial Unfolded Protein Responses in Oxidative Stress-Induced Cataract
AU - Sarah R. Zelle
AU - W. Hayes McDonald
AU - Hassane S. Mchaourab
AU - Kevin L. Schey
PY - 2026
DA - 2026/08/20
PB - bioRxiv
DO - 10.64898/2026.08.19.745850
UR - https://europepmc.org/article/PMC/PMC13722104
AB - Purpose:: Oxidative stress is thought to contribute to the development of age-related cataracts (ARCs), but the mechanisms by which oxidative damage leads to the opacification of the lens remain unclear. Previous studies suggest that oxidative stress can disrupt lens proteostasis. Therefore, it was hypothesized that ARCs arise from proteomic changes driven by an age-associated decline in oxidative stress defenses that interact with the lens proteostatic state. To test this hypothesis, proteomic analyses of lenses exposed to oxidative stress were performed to examine oxidative and proteostatic stress responses in vivo. Methods:: Cataract formation was induced by injecting hydrogen peroxide into the aqueous humor of adult zebrafish. nrf2fh318/fh318 zebrafish were used to model the reduced oxidative stress protection observed in aged human lenses, while cryaba−/− zebrafish were used to model impaired lens proteostasis. Resulting opacities in WT, cryaba−/−, nrf2fh318/fh318, and cryaba−/−; nrf2fh318/fh318 lenses were quantified and proteomic changes in the cortex were analyzed using data independent acquisition Parallel Accumulation Serial Fragmentation mass spectrometry. Results:: Hydrogen peroxide treatment induced the formation of cortical cataracts. Proteomic results showed that, dependent on genotype and day, oxidative stress activates the unfolded and mitochondrial unfolded protein responses. Additional changes were also observed in energy metabolism, Ca2+ homeostasis, protein degradation, and cytoskeletal and extracellular matrix remodeling pathways. Conclusions:: Treated zebrafish lenses successfully model ARC and mass spectrometry proteomics identified the unfolded and mitochondrial unfolded protein responses as potential therapeutic targets for ARC.
SN - 2692-8205
ER -