Metabolic reprogramming and mitochondrial dynamics: Novel therapeutic perspectives for age-related macular...

Age-related macular degeneration (AMD) represents the leading cause of irreversible vision loss in the elderly, affecting over 200 million individuals worldwide. Despite recent advances, therapeutic options remain severely limited, particularly for dry AMD characterized by progressive geographic atrophy. Emerging evidence implicates mitochondrial dysfunction and metabolic reprogramming of retinal pigment epithelium (RPE) cells as central pathogenic drivers. Under pathological conditions, RPE cells exhibit profound bioenergetic collapse marked by declining oxidative phosphorylation, compensatory glycolytic activation, and aberrant tricarboxylic acid cycle intermediate accumulation. This metabolic catastrophe is structurally underpinned by dysregulated mitochondrial dynamics. The resultant accumulation of fragmented, dysfunctional mitochondria perpetuates reactive oxygen species overproduction and mitochondrial DNA damage, establishing a self-amplifying vicious cycle driving RPE degeneration. Mechanistically, this involves dysregulation of the AMPK/mTOR energy-sensing axis, SIRT1/PGC-1α transcriptional control, and Nrf2/ARE antioxidant defenses. Multi-omics profiling reveals distinct metabolic signatures. These discoveries have catalyzed mechanism-based interventions. However, translational applications still face many challenges, and the combination of single-cell multi omics and multimodal therapies is expected to play a role.in restoring mitochondrial homeostasis and preserving vision in aging population in the future.