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

Area of Science:

• Cell Biology
• Ophthalmology
• Aging Research

Background:

• Lens epithelial cells (LECs) are crucial for lens transparency, and their aging contributes to cataract formation.
• Mitochondrial metabolism is a key target for delaying LEC aging.
• La-related protein 1 (LARP1) influences mitochondrial function, but its role in LEC aging is unknown.

Purpose of the Study:

• To investigate the mechanism by which LARP1 affects LEC aging and mitochondrial function.
• To explore LARP1 as a potential therapeutic target for delaying LEC senescence.

Main Methods:

• Induction of LEC senescence using D-galactose.
• LARP1 knockdown using siRNA.
• Assessment of mitochondrial oxidative phosphorylation (OXPHOS) function.
• Analysis of NDUFB8 and SDHB mRNA and protein expression.
• Investigation of stress granule (SG) formation and inhibition.

Main Results:

• LARP1 was significantly upregulated in D-galactose-induced senescent LECs.
• LARP1 knockdown attenuated LEC senescence and restored OXPHOS function.
• LARP1 inhibited NDUFB8 and SDHB expression by binding to their mRNAs and forming SGs, impairing OXPHOS.
• SG inhibitors restored NDUFB8/SDHB translation and reduced senescence markers.

Conclusions:

• LARP1 plays a critical role in LEC senescence by impairing mitochondrial OXPHOS function via SG-mediated translational inhibition.
• Targeting LARP1 and SG formation offers potential strategies to combat LEC aging and delay cataract development.