Recycling of metabolites from ingested outer segments supports visual function

 描述(申请人提供)：正常的视觉功能依赖于RPE-Müler-光感受器细胞之间的密切结构和功能相互作用。光感受器(PR)细胞具有很高的新陈代谢速率，由脉络膜血供的葡萄糖和Müller神经胶质细胞通过有氧糖酵解产生的乳酸支持。新陈代谢底物的一个经常被忽视的来源是由RPE所摄取的光感受器外节(OS)的日常膳食。每天，光感受器细胞在光开始后不久就会脱落大约10%的OSS；然后这些OSS被覆盖在RPE上的吞噬和降解。利用这种富含脂肪酸和蛋白质的OS进行脂肪酸氧化和RPE的酮类合成以前还没有被研究过。因此，我们的长期目标是确定RPE细胞在多大程度上利用OSS不仅满足自身的能量需求，而且支持正常的视觉功能。我们的研究将建立一个基本的了解作为线粒体和过氧化物体(Prx)β氧化底物的OS脂的代谢命运。在这些研究中，我们将检验这样一种假设，即摄入的OS脂用于脂肪酸的β氧化和酮类生成，为神经视网膜提供分解代谢和合成代谢过程的代谢物。我们进一步提出，这些过程是由自噬调节的。在第一个特定的目标中，我们将确定RPE是否使用从脱落的光感受器外段(OS)中提取的脂类来进行脂肪酸β氧化(FAO)和酮的生成。我们随后将确定BHB在维持RPE、光感受器细胞和Müler细胞(MC)健康和功能方面的作用。我们将通过确定自噬途径如何影响OS用于酮的生成来遵循这些过程的调节。总之，这些研究提供了OS降解和脂肪酸代谢之间的新的机制联系，并深入了解了线粒体功能障碍如何导致在年龄相关性视网膜退化中观察到的脂质碎片的积累。

 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.