Photobiomodulation in Age-Related Macular Degeneration: A Mitochondrial Bioenergetic Framework and Translational...

Background/Objectives: Age-related macular degeneration (AMD) is a leading cause of irreversible visual impairment in aging populations. While effective treatments exist for neovascular AMD and, more recently, geographic atrophy, no widely accepted therapy prevents disease progression in earlier stages. Photobiomodulation (PBM) has emerged as a potential approach to modulate retinal metabolism. This review examines the biological mechanisms proposed to explain PBM effects and explores how mitochondrial physiology may support a bioenergetic framework linking these mechanisms to retinal function in AMD. Methods: We conducted a targeted review of experimental and clinical literature addressing photobiomodulation, mitochondrial function, and retinal metabolism in AMD. Results: Experimental studies indicate that PBM may influence mitochondrial activity through multiple mechanisms, including modulation of cytochrome c oxidase, nitric oxide photodissociation, and redox signaling pathways. However, the diversity of mechanisms and variability of clinical outcomes suggest that the biological basis of PBM remains incompletely understood. Emerging insights from mitochondrial physiology, including the debated concept of local thermal microenvironments, support interpreting PBM effects as modulation of mitochondrial bioenergetics rather than isolated molecular pathways. Conclusions: We propose a conceptual framework in which PBM responses are governed by the interaction between a dose-dependent bioenergetic window and the mitochondrial functional reserve of retinal cells. Within this model, therapeutic effects are most likely when PBM is delivered within an optimal range of stimulation and in retinal tissues where mitochondrial dysfunction remains partially reversible. This framework may help explain variability across studies and support more rational use of PBM in early and intermediate AMD.