DESCRIPTION (provided by applicant): Normal visual function is dependent on the intimate structural and functional interactions amongst RPE-Müller-photoreceptor cells. Photoreceptor (PR) cells have a high rate of metabolism that is supported by glucose from the choroidal blood supply and lactate produced by Müller glial cell through aerobic glycolysis. An often overlooked source of metabolic substrates is the daily meal of photoreceptor outer segments (OS) taken up by the RPE. On a daily basis, photoreceptors cells shed approximately 10% of their OSs shortly after light onset; these are then phagocytosed and degraded by the overlaying RPE. Utilization of this fatty acid and protein rich OS for fatty acid oxidation and ketogenesis by the RPE has not previously been investigated. Thus, our long term goal is to determine to what extent RPE cells utilize OSs for not only their own energy needs but also in supporting normal visual function. Our studies will establish a fundamental understanding of the metabolic fate of OS lipids as substrates for mitochondrial and peroxisomal (Prx) β-oxidation. In these studies we will test the hypothesis that ingested OS lipids are used for fatty acid β-oxidation and ketogenesis to supply metabolites to the neural retina for catabolic and anabolic processes. We further propose that these processes are regulated by autophagy. In the first Specific aim we will determine if the RPE uses lipids from shed photoreceptor outer segments (OS) for fatty acid β-oxidation (FAO) and ketogenesis. We will subsequently determine the role of BHB in maintaining RPE, photoreceptor cell and Müller cell (MC) heath and function. We will follow regulation of these processes by determining how autophagic pathways affect the utilization of OS for ketogenesis. Collectively, these studies provide a novel mechanistic link between OS degradation and fatty acid metabolism and insight into how mitochondrial dysfunction could contribute to the accumulation of lipid debris observed in age related retinal degeneration.

PUBLIC HEALTH RELEVANCE: As phagocytes, retinal pigment epithelial (RPE) cells function as a homeostatic regulator to maintain photoreceptor integrity and preserve visual function. These metabolically active cells utilize ingested lipids components to generate energy in the form of ketone bodies including β-hydroxybutyrate. In these studies we will investigate a novel metabolic coupling pathway in which the ketones generated by the RPE are utilized to support photoreceptor cell function.