Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Its pathogenesis remains incompletely understood, partly due to the complex interplay of genetic risk, aging, and environmental stressors. Cigarette smoking (CS) is a major modifiable risk factor for AMD, yet the mechanism linking CS to disease progression remains unclear. We hypothesize that CS accelerates AMD pathogenesis by exacerbating cellular senescence in the retinal pigment epithelium (RPE), thereby driving age-related RPE dysfunction and degeneration. In this study, differentiated ARPE-19 cells or mice were exposed to low-dose cigarette smoke condensate (CSC), and stress-induced senescence-like RPE phenotypes were induced, characterized by increased senescence markers, mitochondrial dysfunction, and retinal functional impairment. RPE senescence phenotypes were also confirmed in mice exposed to 6 months of CS in the smoking chamber. CSC-induced RPE senescence was associated with a biphasic alteration in mitochondrial morphology, progressing from early mitochondrial fragmentation to late mitochondrial hyperfusion, as well as impaired mitophagy flux, reduced mitochondrial turnover, and decreased mitochondrial biogenesis. Mechanistically, CSC increased dynamin-related protein 1 (DRP1) phosphorylation and promoted cleavage of the mitochondrial phosphatase PGAM5, mitochondrial remodeling associated with decreased DRP1 activities, elevated mitochondrial oxidative stress, and activation of mTOR signaling. Notably, overexpression of a DRP1 activity mutant (K38A) mimics the CSC-induced RPE senescence, while overexpression of the phosphodeficient DRP1-S637A mutant significantly attenuates both mTOR signaling and CSC-induced RPE senescence by restoring mitochondrial fission balance, improving mitochondrial quality-control responses, reducing mitochondrial oxidative stress. Collectively, these findings identify impaired DRP1-dependent mitochondrial remodeling as a key mechanism linking CSC exposure to RPE senescence. While we confirmed the RPE senescence phenotype in mice after 6 months of CS exposure, the specific mechanisms observed in this study require further validation in a chronic CS model. These findings encourage future research into mitochondrial dynamics and RPE senescence in AMD, suggesting that modulating RPE mitochondrial dynamics holds therapeutic potential for delaying AMD progression.
