Cellular Localization of FOXO3 Determines Its Role in Cataractogenesis

Area of Science:

• Cell Biology
• Ophthalmology
• Molecular Biology

Background:

• Forkhead box protein O3 (FOXO3) regulates cellular homeostasis and stress response.
• FOXO3's function is closely tied to its cellular localization.
• Cataract formation involves cellular changes in lens epithelial cells (LECs).

Purpose of the Study:

• To investigate the role of FOXO3 in cataractogenesis.
• To explore the effect of hydrogen (H2) on FOXO3 localization and function in LECs.
• To determine the therapeutic potential of H2 in a rat cataract model.

Main Methods:

• Examined FOXO3 localization in human cataract tissues and MNU-induced rat cataracts.
• Utilized MNU-injured human LEC (HLEC) lines for molecular analysis.
• Assessed gene expression related to cell cycle arrest and apoptosis.
• Investigated the effect of H2 treatment on FOXO3 translocation and mitochondrial function.
• Evaluated H2's efficacy in an MNU-induced rat cataract model.

Main Results:

• FOXO3 exhibited nuclear translocation in LECs from cataract tissues and MNU-injured HLECs.
• FOXO3 knockdown inhibited MNU-induced expression of cell cycle arrest and apoptosis genes.
• H2 treatment induced MAPK1-mediated cleavage and mitochondrial translocation of FOXO3 in HLECs.
• H2 increased mitochondrial DNA (mtDNA) transcription and stabilized mitochondrial function in HLECs.
• H2 treatment ameliorated MNU-induced cataracts in a rat model.

Conclusions:

• FOXO3 localization correlates with its function in cataract formation.
• H2 protects HLECs from injury by promoting FOXO3 mitochondrial translocation via MAPK1 activation.
• Mitochondrial FOXO3 enhances mtDNA transcription and stabilizes mitochondrial function, offering a protective mechanism against cataract development.