Dynamic metabolism between the retinal pigmented epithelium and retina reveals a metabolic ecosystem in the eye

Thesis (Ph.D.)--University of Washington, 2019There are a collection of specialized neurons and glia in the retina that convert visible light that enters the eye into chemical signals that stimulate biological processes that contribute to our visual perception. Photoreceptors are the light sensitive neurons of the retina that kickoff this process. They are a highly polarized cell that must produce large amounts of energy to maintain their polarity and detect the absence or presence of light. There exist metabolic adaptations between them, the retinal pigmented epithelium (RPE) and Müller glia cells (MGCs) of the retina. These metabolic adaptations enhance the flow of glucose from the choroid through the RPE to rod and cone photoreceptors to promote retinal function and survivability. In age-related, or inherited retinal diseases such as retinitis pigmentosa, it’s been observed that photoreceptor degeneration and death occurs when these specific metabolic adaptations are disturbed. We investigated a metabolic flux model in photoreceptors and the RPE using a variety of analytical techniques that include: mass spectrometry, confocal immunofluorescence imaging, and animal imaging of mouse and zebrafish retina and cultured human fetal RPE cells (hfRPE). In our model, we found that considerable amounts of glucose traverse through the RPE in mouse and zebrafish eye towards the retina, and that glucose enters the retina through photoreceptors. Photoreceptors are highly glycolytic and convert the glucose into lactate to meet their energy demands. Photoreceptor lactate can then be exported to the RPE and neighboring MGCs. We used cultured human fetal RPE cells to identify that lactate can suppress the consumption of glucose by the RPE to allow for its utilization by the retina. With the consumption of glucose suppressed in the RPE, it can allow for increased amounts of glucose to reach the retina from the choroidal blood supply. Additionally, we identified that the RPE is capable of storing excess glucose in the form of glycogen possibly for feeding the retina when circulating glucose levels are low. Altogether, these findings provide a foundation for understanding the metabolic relationships in the retina that can be applied towards new concepts of novel strategies for preventing photoreceptor degeneration and blindness