Recycling of Metabolites from Ingested Outer Segments Supports Visual Function

视觉功能取决于结构、功能和代谢之间的密切相互作用 视网膜色素上皮（RPE）和神经视网膜。感光细胞 (PR) 具有很高的 通过持续供应葡萄糖和氧气来支持新陈代谢率 脉络膜血管系统。 RPE 形成外血视网膜屏障并将葡萄糖转运至 外视网膜通过顶膜和基底外侧膜中的 GLUT1 转运蛋白。视网膜色素上皮 通过氧化有氧糖酵解产生的乳酸，为外视网膜节省葡萄糖 外视网膜和来自摄入的光感受器外节（OS）的脂肪酸。因此， 我们假设 RPE 通过以下方式充当视网膜代谢稳定性的守门人： 生物能量学专业，可增强视网膜燃料可用性并支持感光器 功能。在这一角色中，终生维持 RPE 功能至关重要，特别是考虑到 这些细胞是有丝分裂后的。 RPE 氧化脂肪酸和乳酸维持其 氧化代谢的变化导致 RPE 去分化，从而影响分化和 PR 功能。 我们假设脂肪酸氧化 (FAO) 的有益作用与 生酮将 (1) 为 RPE 提供能量并防止脂肪变性 (2) 再氧化线粒体 NADH 促进乳酸利用，(3) 减少 RPE 对葡萄糖的依赖，从而避免其 (4) 通过 βHB 的酮解作用为 PR 提供燃料。此外，我们 假设乳酸不仅是 RPE 中能量生产的燃料，而且是乳酸的副产品 氧化调节溶酶体 pH 值和基因转录。我们的长期目标是确定 控制外视网膜代谢共生的途径，以维持正常视力 一生。这些假设将在以下具体目标中进行检验。具体目标1：确定 长链脂肪酸的氧化是否是维持代谢稳态所必需的 RPE 的分化。具体目标 2：确定 RPE 的协调活动如何 生酮和 PR 酮解支持视觉功能。具体目标 3：确定是否 PR 和外视网膜 Müller 神经胶质细胞有氧糖酵解产生的乳酸支持 RPE 代谢和分化以及溶酶体 pH 值的维持。总的来说，这些研究 证明外层代谢特化细胞之间的共生关系 视网膜。 RPE、PR 或 Müller 细胞的损伤可导致非自主变化， 对整个系统产生负面影响并导致视力丧失。

Visual function depends on the intimate structural, functional and metabolic interactions between the retinal pigment epithelium (RPE) and the neural retina. Photoreceptor (PR) cells have a high rate of metabolism that is supported through a continuous supply of glucose and oxygen from the choroidal vasculature. The RPE forms the outer blood retinal barrier and transports glucose to the outer retina via GLUT1 transporters in both the apical and basolateral membranes. The RPE spares glucose for the outer retina by oxidizing lactate generated through aerobic glycolysis in the outer retina and fatty acids derived from ingested photoreceptor outer segments (OS). Thus, we hypothesize that the RPE serves as the gatekeeper of retinal metabolic stability through bioenergetics specializations that enhance retinal fuel availability and support photoreceptor function. In this role, it is critical that RPE function be maintained over a lifetime, especially given that these cells are post-mitotic. RPE oxidation of fatty acids and lactate maintains its differentiation and PR function as changes in oxidative metabolism lead to RPE dedifferentiation. We hypothesize that the beneficial effects of fatty acid oxidation (FAO) working in synergy with ketogenesis will (1) provide energy for the RPE and prevent steatosis (2) reoxidize mitochondrial NADH to facilitate lactate utilization, (3) decrease RPE reliance on glucose thereby sparing it for the neural retina and (4) provide fuel for PR through ketolysis of βHB. Furthermore, we hypothesize that lactate is not only a fuel for energy production in RPE, but by-products of lactate oxidation regulate lysosomal pH and gene transcription. Our long-term goal is to identify the pathways that control metabolic symbiosis in the outer retina to sustain normal vision over a lifetime. The hypotheses will be tested in the following specific aims. Specific aim 1: To determine whether oxidation of long chain fatty acids is necessary to maintain metabolic homeostasis and differentiation of the RPE. Specific Aim 2: To determine how the coordinated activities of RPE ketogenesis and PR ketolysis support visual function. Specific Aim 3: To determine whether lactate produced through aerobic glycolysis in PR and Mϋller glia in the outer retina supports RPE metabolism and differentiation as well as maintenance of lysosomal pH. Collectively these studies demonstrate the symbiotic relationship among the metabolically specialized cells in the outer retina. Damage to the RPE, PR or Mϋller cells can cause non-autonomous changes that negatively affect the entire system and lead to vision loss.