New Insights into the Roles of Glutaredoxins in the Lens




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Glutaredoxins (Grxs) play a crucial role in reversing protein glutathionylation. Glutaredoxin 1 (Grx1) and Glutaredoxin 2 (Grx2) are two main members of Grxs. Our prior studies have demonstrated that the Grx1 and Grx2 double knockout (DKO) mice develop cataracts prematurely at three months of age, and they are more susceptible to UV radiation. Therefore, these findings have highlighted the importance of Grx1 and Grx2 in preserving the transparency of the lens. However, the precise mechanisms underlying the faster development of cataracts in response to simultaneous deletion of Grx1 and Grx2 remain unknown. Lens epithelial cells (LECs) are pivotal for preserving lens transparency and overall lens functionality. Consequently, a comprehensive understanding of the antioxidant defenses and cell repair mechanisms in LECs is vital for cataract prevention and treatment strategies. We hypothesized that the absence of Grx1 and Grx2 could alter LECs function, triggering cataractogenesis. To test the hypothesis, we isolated primary LECs from WT and DKO mice and conducted a range of in vitro experiments to assess the effects of Grxs deletion on the epithelial phenotype, cellular proliferation, apoptosis, and mitochondrial function in LECs. We also conducted histology analysis of lens tissues using hematoxylin and eosin (H&E) staining. Our results revealed that Grx1 and Grx2 deficiency altered epithelial phenotype, reduced proliferation rate, and aberrant cell cycle distribution of DKO LECs compared to WT LECs. The deficiency also induced cellular senescence in cultured DKO LECs, which is consistent with our H&E staining data showing that LECs in the lens tissue from DKO mouse had accelerated senescence. Additionally, DKO LECs displayed compromised mitochondrial function and a compensatory metabolic shift towards glycolysis, indicating an adaptive response to Grx deficiency. Importantly, we also found that the OHPy2N2 activated Grxs and prevented the lens from H2O2-induced lens opacification. In conclusion, the findings in this study indicate that Grxs are important in regulating the aging process in the lens. Compounds that can activate Grxs may be promising candidates for preventing cataracts.