A critical role for mitochondrial dynamics in cigarette smoke condensate-induced RPE senescence

Area of Science:

• Ophthalmology
• Cell Biology
• Gerontology

Background:

• Age-related macular degeneration (AMD) is a leading cause of elderly blindness.
• Cigarette smoking (CS) is a major modifiable risk factor for AMD, but the underlying mechanisms are unclear.
• Cellular senescence in the retinal pigment epithelium (RPE) is implicated in AMD pathogenesis.

Purpose of the Study:

• To investigate the hypothesis that CS accelerates AMD by exacerbating RPE cellular senescence.
• To elucidate the role of mitochondrial dynamics and related signaling pathways in CS-induced RPE senescence.

Main Methods:

• Exposure of differentiated ARPE-19 cells and mice to cigarette smoke condensate (CSC) or CS.
• Assessment of RPE senescence markers, mitochondrial morphology and function, and mitophagy flux.
• Analysis of dynamin-related protein 1 (DRP1) phosphorylation, PGAM5 cleavage, mTOR signaling, and mitochondrial oxidative stress.

Main Results:

• CSC exposure induced RPE senescence phenotypes, including mitochondrial dysfunction and impaired mitophagy.
• CSC altered mitochondrial morphology biphasically (fragmentation to hyperfusion) and reduced mitochondrial turnover.
• Impaired DRP1-dependent mitochondrial remodeling, increased oxidative stress, and mTOR activation were observed in CSC-exposed RPE.
• Modulating DRP1 activity (K38A mutant mimicking senescence, S637A mutant attenuating senescence) confirmed its role in RPE senescence.

Conclusions:

• Impaired DRP1-dependent mitochondrial remodeling is a key mechanism linking cigarette smoke exposure to RPE senescence.
• Mitochondrial dynamics and RPE senescence are critical factors in AMD pathogenesis.
• Targeting RPE mitochondrial dynamics may offer therapeutic potential for delaying AMD progression.