Am J Pathol. 2023 Jul 28:S0002-9440(23)00269-9. doi: 10.1016/j.ajpath.2023.06.016. Online ahead of print.
The transcription factor FOXO3 is a core regulator of cellular homeostasis, stress response, and longevity. The cellular localization of FOXO3 is closely related to its function. Here, we explored the role of FOXO3 in cataract formation. FOXO3 showed nuclear translocation in lens epithelial cells arranged in a single layer on lens capsule tissues from both human cataract and N-methyl-N-nitrosourea (MNU)-induced rat cataract, also in MNU-injured human lens epithelial cell lines (HLECs). FOXO3 knockdown inhibited the MNU-induced increase in expression of genes related to cell cycle arrest (GADD45α and CCNG2) and apoptosis (Bak and TP53). H2 is highly effective in reducing oxidative impairments in nuclear DNA and mitochondria. When we applied H2 to MNU-injured HLECs, FOXO3 underwent cleavage by MAPK1 and translocated into mitochondria, thereby increasing the transcription of oxidative phosphorylation-related genes (MTCO1, MTCO2, MTND1, and MTND6) in HLECs. Furthermore, H2 mediated the translocation of FOXO3 from the nucleus to the mitochondria within the lens epithelial cells of cataract capsule tissues of rats exposed to N-methyl-N-nitrosourea (MNU). This intervention ameliorated MNU-induced cataracts in the rat model. In conclusion, we demonstrated the correlation between the localization of FOXO3 and its function in cataract formation. We also determined that H2 protects HLECs from injury by leading FOXO3 mitochondrial translocation via MAPK1 activation. Mitochondrial FOXO3 can increase mtDNA transcription, stabilize mitochondrial function in HLECs.