Metabolic function in the ocular ecosystem relies on interactions between the retina and retinal pigment epithelium and remains robust in aging

Abstract

The vertebrate eye is a unique ecosystem comprised of a myriad of different cells that all function in concert to facilitate vision. The electrical signal in the eye that is transmitted to the brain begins with the retina, an ordered structure made up of glia and neurons. Highly specialized photoreceptor neurons begin that signaling cascade when struck by light. Photoreceptors interact constantly with the neighboring retinal pigment epithelium (RPE) which replenishes signaling molecules needed for photoreceptor signal transduction. However, these cells are also metabolically intertwined. When photoreceptors start to die, the RPE frequently goes with them, and the inverse has also been found. To better understand the metabolic adaptations and complex interplay between these two specialized cell-types, we examined the eye in health and under stress. In a normal vertebrate eye, we found that the retina and retinal pigment epithelium have cooperative metabolic strategies that differ significantly from expected paradigms seen in the brain. The retina is known to be glycolytic, while the RPE appears to rely more on its mitochondria. We found that it is specifically photoreceptor neurons that are consuming glucose. Significant quantities of lactate are exported by the retina. The RPE appears to prefer lactate over glucose as a fuel. This indicates that the RPE passes along glucose to the retina, which generates lactate and exports it for the RPE to consume. While the retina predominantly relies on glycolysis, the size, quantity, distribution, and complexity of the mitochondria in photoreceptors were found to be incredibly dynamic depending upon circadian rhythm. Nightfall brought large, mitochondrially-connected networks and increased metabolic flux through succinate dehydrogenase. We used a targeted GC-MS assay to probe the metabolic capacity of retina and RPE-choroid-sclera complexes (eyecup) when provided 13C-labeled glucose or glutamine. The metabolism of the retina and eyecups appear to be remarkably resilient to stress. Mutations in NNT and Rd8, which effect metabolism and cellular structure, respectfully, do not impact reductive flux from glutamine. Advanced age also did not severely impact the metabolic capacity of either tissue. We identified a defect in glutamine metabolism of eyecups and a trend towards lower glutamine-driven OCR. Otherwise, glucose uptake, glucose flux, anaplerotic flux, and amino acid pools were unaffected in retinas and eyecups with age. Given the known functional decline of vision which we were able to confirm using electroretinograms in aged mice, the near complete lack of change with age was intriguing. Future studies of the aged eye should consider the application of additional in vivo approaches to metabolic characterization. This will confirm if the intrinsic stability of these tissues’ metabolism holds in the less hospitable environment of the aging eye and may still represent a viable treatment option for age-related vision loss and blindness.