Influences of Calcium and Oxygen on Retinal Metabolism

Thesis (Ph.D.)--University of Washington, 2021Photoreceptors require an excessive amount of energy to carry out their function, yet their access to the nutrients and oxygen which could facilitate efficient ATP production is restricted by neighboring retinal pigment epithelial (RPE) cells. This dissertation investigates the metabolic adaptations made by both photoreceptors and RPE which allow both cell types to coexist in a competitive environment, with a focus on understanding the independent influences of mitochondrial Ca2+ uptake and O2 tension. Highly specialized photoreceptors in the retina use Ca2+ as a second messenger to transduce light to a chemical signal, yet we find that mitochondrial Ca2+ uptake mediated by the Mitochondrial Ca2+ Uniporter is quite dispensable for photoreceptor metabolism and function. Instead, we find that photoreceptor metabolism appears to be programmed by the basal hypoxic niche they normally reside in, which causes photoreceptors produce succinate by non-canonical reversal of succinate dehydrogenase. This succinate is exported from retinas by Monocarboxylate Transporter 1 (MCT1) and is capable of being imported and oxidized by eyecup tissue, which has ample access to O2 in the eye. Transport of succinate between tissues may be more widespread than previously thought, as we also uncover evidence that succinate can be oxidized in cerebellum, kidney, liver, and brown adipose tissue