Rethinking aerobic metabolism in retinal rod outer segments: Triple metabolic hypothesis and clinical implications

The vertebrate retina is among the most energy-demanding tissues in the body, with photoreceptors accounting for most of its metabolic activity. The photoreceptor outer segment, devoid of mitochondria, carries out visual transduction. Oxidative phosphorylation in the rod inner segment has been considered the primary source of ATP in the photoreceptor; however, the bioenergetic requirements of the outer segment remain insufficiently explained. Models based on glycolysis, metabolite diffusion, and lactate shuttling do not fully account for the rapid energy demands of phototransduction and recovery in the outer segment. The rod requires local, timely metabolic support of opposite bioenergetic demands during the light/darkness cycle. In this review, we revisit the bioenergetics of rod outer segments by integrating historical biochemical data, proteomic and functional evidence, and new data suggesting the presence of oxidative metabolic processes within outer segment disks. We propose a compartmentalized metabolic structure in which inner segment mitochondria, aerobic glycolysis, and a putative ectopic oxidative phosphorylation system in the outer segment in a triple metabolic mechanism, to supply their localized and divergent ATP demands. We examine how this metabolic organization influences redox balance and how its disruption may explain their vulnerability in aging and disease. We also discuss the crosstalk between the outer segments and the retinal pigment epithelium, establishing a pro-oxidative condition in the outer retina as well as the effects of localized oxidative stress in many acquired retinal dystrophies. This perspective revisits the conventional view that oxidative phosphorylation in photoreceptors is restricted to inner segment mitochondria and highlights new directions for investigating retinal bioenergetics and pathophysiology.