Targeting LARP1 to mitigate aging in lens epithelial cells: mechanistic insights into mitochondrial dysfunction.

Abstract

As we age, lens epithelial cells (LECs) undergo various stressors, contributing to cataract development. Targeting the regulation of mitochondrial metabolism may be an effective strategy to delay LEC aging. La-related protein 1 (LARP1) is an RNA-binding protein that affects mitochondrial function by regulating mRNA stability and translation. However, the specific mechanism underlying the role of LARP1 in LEC aging is unclear. In the present study, we found that LARP1 was significantly upregulated during D-galactose-induced senescence in LECs. LARP1 knockdown significantly attenuated cellular senescence and restored mitochondrial oxidative phosphorylation (OXPHOS) function. Further studies revealed that the upregulation of LARP1 inhibited the expression of the nuclear-encoded OXPHOS subunits NDUFB8 and SDHB, thereby impairing OXPHOS function. LARP1 inhibited translation of NDUFB8 and SDHB mRNAs by binding to these mRNAs and forming stress granules (SGs). In the presence of SG inhibitors, the translation levels of NDUFB8 and SDHB were restored, and cellular senescence markers were significantly reduced. In conclusion, the present study revealed the critical role of LARP1 in LEC senescence, suggesting that it impairs mitochondrial OXPHOS function through SG-mediated translational inhibition, which provides new insights into the mechanism of mitochondrial dysfunction in LEC senescence, as well as new intervention strategies to resist LEC senescence.