Ubiquitination of Ku70 by Parkin promotes apoptosis of lens epithelial cells

Oxidative damage‐triggered apoptosis in lens epithelial cells is considered as a main risk factor in the pathogenesis of age‐related cataracts. Ku70 is a key factor in the DNA repair process of double‐strand breaks. In the present study, we aimed to investigate the role of Ku70 and its related E3 ubiquitin ligase in lens epithelial cell apoptosis. The levels of Ku70 in the anterior lens capsules of human cataracts and Emory mice were lower compared to controls. H2O2 treatment resulted in decreased expression of Ku70 through accelerating Ku70 ubiquitination. Parkin, an E3 ubiquitin ligase, could interact with Ku70 and promote the ubiquitination and degradation of this protein. In addition, ubiquitinated Ku70 was regulated by ubiquitin‐proteasome, autophagy‐lysosome and mitophagy pathways. Ectopic expression of Ku70 protected SRA01/04 cells from H2O2‐induced apoptosis, whereas silencing Ku70 exhibited the opposite trend. Co‐transfected with Parkin non‐ubiquitinatable Ku70 mutant could maintain its anti‐apoptosis ability, whereas wild‐type Ku70 failed. Moreover, Ku70 might facilitate mitochondrial fusion by increasing the expression of Mitofusin 1/2. The present study revealed that Parkin‐mediated Ku70 ubiquitination facilitated H2O2‐induced lens epithelial cell apoptosis through alleviating mitochondrial fusion, which could provide potential targets for age‐related cataract treatment. Our study demonstrates that decreased Ku70 levels are associated with age‐related cataracts. Ku70 serves an anti‐apoptotic role in H2O2‐simulated cells, whereas the E3 ubiquitin ligase Parkin prevents Ku70 function via ubiquitination. Additionally, ubiquitinated Ku70 is regulated by the ubiquitin‐proteasome, autophagy‐lysosome and mitophagy pathways. Moreover, Ku70 prevents apoptosis through facilitating mitochondrial fusion. Our data suggest that Ku70 and Parkin can be targeted for the development of effective therapies for age‐related cataracts.