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首页> 外文期刊>Redox Biology >Mitochondrial oxidative stress in the retinal pigment epithelium (RPE) led to metabolic dysfunction in both the RPE and retinal photoreceptors
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Mitochondrial oxidative stress in the retinal pigment epithelium (RPE) led to metabolic dysfunction in both the RPE and retinal photoreceptors

机译：视网膜色素上皮（RPE）中的线粒体氧化应激导致RPE和视网膜感光细胞的代谢功能障碍

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Age-related macular degeneration (AMD) is the leading cause of vision loss in the western world. Recent evidence suggests that RPE and photoreceptors have an interconnected metabolism and that mitochondrial damage in RPE is a trigger for degeneration in both RPE and photoreceptors in AMD. To test this hypothesis, this study was designed to induce mitochondrial damage in RPE in mice to determine whether this is sufficient to cause RPE and photoreceptor damage characteristic of AMD. In this study, we conditionally deleted the gene encoding the mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD encoded by Sod2 ) in the retinal pigment epithelium (RPE) of albino BALB/cJ mice. VMD2-Cre;Sod2 sup flox/flox /sup BALB/cJ mice were housed in either 12-h dark, 12-h 200 lux white lighting (normal light), or 12-h dark, 12-h 10 lux red lighting (dim light). Electroretinography (ERG) and spectral-domain optical coherence tomography (SD-OCT) were performed to assess retinal function and morphology. Immunofluorescence was used to examine protein expression; quantitative RT-PCR was used to measure gene expression. Sod2 knockout (KO) mice had reduced RPE function with age and increased oxidative stress compared to wild type (WT) controls as expected by the cell-specific deletion of Sod2. This was associated with alterations in RPE morphology and the structure and function of RPE mitochondria. In addition, data show a compensatory increase in RPE glycolytic metabolism. The metabolic shift in RPE correlated with severe disruption of photoreceptor mitochondria including a reduction in TOMM20 expression, mitochondrial fragmentation, and reduced COXIII/β-actin levels. These findings demonstrate that mitochondrial oxidative stress can lead to RPE dysfunction and metabolic reprogramming of RPE. Secondary to these changes, photoreceptors also undergo metabolic stress with increased mitochondrial damage. These data are consistent with the hypothesis of a linked metabolism between RPE and photoreceptors and suggest a mechanism of retinal degeneration in dry AMD.
机译：与年龄有关的黄斑变性（AMD）是西方世界视力丧失的主要原因。最近的证据表明，RPE和光感受器具有相互关联的代谢，RPE中的线粒体损伤是AMD中RPE和光感受器两者变性的触发因素。为了检验这一假设，本研究旨在诱导小鼠RPE中的线粒体损伤，以确定其是否足以引起AMD的RPE和感光受体损伤。在这项研究中，我们有条件地删除了白化BALB / cJ小鼠的视网膜色素上皮（RPE）中编码线粒体抗氧化酶的基因，锰超氧化物歧化酶（Sod2编码的MnSOD）。将VMD2-Cre; Sod2 flox / flox BALB / cJ小鼠饲养在12小时黑暗，12小时200 lux的白光（正常光照）或12小时黑暗，12小时< 10 lux红色照明（昏暗的灯光）。进行了视网膜电图（ERG）和光谱域光学相干断层扫描（SD-OCT），以评估视网膜功能和形态。免疫荧光检测蛋白表达。定量RT-PCR用于测量基因表达。与野生型（WT）对照相比，Sod2敲除（KO）小鼠的RPE功能随着年龄的增长而降低，氧化应激增加，这是由于Sod2的细胞特异性缺失所预期的。这与RPE形态以及RPE线粒体的结构和功能的改变有关。另外，数据显示RPE糖酵解代谢的补偿性增加。 RPE的代谢变化与光感受器线粒体的严重破坏有关，包括TOMM20表达减少，线粒体片段化和COXIII /β-肌动蛋白水平降低。这些发现证明线粒体的氧化应激可导致RPE功能障碍和RPE的代谢重编程。继这些变化之后，光感受器也会经历代谢应激，并增加线粒体损伤。这些数据与RPE和感光细胞之间的连锁代谢假说相符，并提示了干性AMD中视网膜变性的机制。

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