Metabolic signatures of cone-dominant and cone-degenerating retinas
This study highlights significant metabolic changes in cone-dominant and degenerating retinas, particularly increases in glutathione and aminoadipate, which may indicate metabolic vulnerabilities in retinal health.
Where it sits
this study against the rest of the glutathione (gsh) corpusSummary and findings
This study investigated cone-specific metabolism in cone-dominant and cone-degenerating mouse models, including Nrl -/- and Cnga3 -/- models, with a focus on metabolic changes in the retinal pigment epithelium. The research found increases in glutathione and several amino acids, alongside decreases in pyruvate and uracil. The findings suggest potential metabolic vulnerabilities associated with cone degeneration.
Abstract
Cone photoreceptors are essential for daylight vision, and their degeneration has more profound visual consequences than rod loss in retinal degenerative diseases. Metabolic dysfunction is closely associated with cone degeneration, however the relatively small population of cones in mice and humans have limited our understanding of cone-specific metabolism. Here, we leveraged cone-dominant and cone-degeneration mouse models including Nrl -/- , Cnga3 -/- , and high-dose Triiodothyronine (T3) treatment to investigate cone-specific metabolism and their metabolic impacts on the retinal pigment epithelium (RPE). Across models, cone-dominant retinas consistently showed lower pyruvate abundance alongside increases in glutathione, purines, pentose phosphate pathway intermediates, and one-carbon metabolites. Increases in several key amino acids were also associated with higher cone abundance, such as proline, arginine, alanine, valine, leucine, and hypotaurine. Strikingly, aminoadipate, an intermediate in lysine catabolism, was the most robustly changed metabolite in the retina, showing highly consistent increases across models. Relative cone increases were also associated with metabolic changes in the RPE/choroid. Like the retina, RPE/choroids showed consistent increases in aminoadipate, proline, and hypotaurine, as well as xanthosine and betaine, alongside decreases in uracil. Moreover, proteomic analysis of Nrl -/- mice showed decreases in many key metabolite transporters in the RPE/choroid, including carriers for glucose, lactate, aspartate, glutamate, serine, lysine, taurine, and proline. Collectively, these findings further our understanding of cone-specific metabolism and highlight potential cone-specific metabolic vulnerabilities in retinal degeneration.