FUNDC1 deficiency aggravates endothelial senescence and retinal dysfunction.

Abstract

Natural aging leads to various age-related changes that impair visual function and cause ocular diseases. Endothelial cells, key components of blood vessels, play a crucial role in vascular aging and retinal degeneration. However, the exact mechanisms by which endothelial cell aging promotes retinopathy are not fully understood. Mitochondrial homeostasis is vital for endothelial cell function, with mitophagy being essential for removing damaged mitochondria. FUNDC1, a receptor involved in mitophagy, regulates cellular senescence and inflammation. This study investigates whether retinal function decline is linked to mitochondrial imbalance in retinal vessels endothelial cells due to reduced FUNDC1 expression. In aged mice, FUNDC1 expression and mitophagy were significantly lower in retinal blood vessels. Aging leads to retinal vascular dysfunction characterized by increased vascular permeability assessed by fluorescein fundus angiography. Moreover, electron microscopy images showed mitochondrial swelling in endothelial cells of aging retina, accompanied with tight junction disruption and reduced expression of junctional proteins (VE-cadherin, occludin, and ZO-1). Strikingly, endothelial knockout of FUNDC1 exacerbated the age-related decline in retinal blood vessel function and retinal function. Cell senescence induced by D-galactose exhibited significantly decreased FUNDC1, impaired mitophagy, increased reactive oxygen species (ROS), and markedly increased endothelial permeability assessed by transendothelial electrical resistance assay. Conversely, overexpression of FUNDC1 can reverse the reduction of mitochondrial autophagy, the decrease in intercellular junction protein expression and the increase in endothelial permeability caused by aging. Collectively, these data suggest that FUNDC1 serves as a potential therapeutic target for the prevention and treatment of age-related degeneration of retinal function.