Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people in the developed world, and the number of people affected is expected to almost double by 2040. The retina presents one of the highest metabolic demands in our bodies that is partially or fully fulfilled by mitochondria in the neuroretina and retinal pigment epithelium (RPE), respectively. Together with its post-mitotic status and constant photooxidative damage from incoming light, the retina requires a tightly-regulated housekeeping system that involves autophagy. The natural polyphenol Urolithin A (UA) has shown neuroprotective benefits in several models of aging and age-associated disorders, mostly attributed to its ability to induce mitophagy and mitochondrial biogenesis. Sodium iodate (SI) administration recapitulates the late stages of AMD, including geographic atrophy and photoreceptor cell death. A combination of in vitro, ex vivo and in vivo models were used to test the neuroprotective potential of UA in the SI model. Functional assays (OCT, ERGs), cellular analysis (flow cytometry, qPCR) and fine confocal microscopy (immunohistochemistry, tandem selective autophagy reporters) helped address this question. UA alleviated neurodegeneration and preserved visual function in SI-treated mice. Simultaneously, we observed severe proteostasis defects upon SI damage induction, including autophagosome accumulation, that were resolved in animals that received UA. Treatment with UA restored autophagic flux and triggered PINK1/Parkin-dependent mitophagy, as previously reported in the literature. Autophagy blockage caused by SI was caused by severe lysosomal membrane permeabilization. While UA did not induce lysosomal biogenesis, it did restore upcycling of permeabilized lysosomes through lysophagy. Knockdown of the lysophagy adaptor SQSTM1/p62 abrogated viability rescue by UA in SI-treated cells, exacerbated lysosomal defects and inhibited lysophagy. Collectively, these data highlight a novel putative application of UA in the treatment of AMD whereby it bypasses lysosomal defects by promoting p62-dependent lysophagy to sustain proteostasis.

中文翻译：

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尿石素 A 促进 p62 依赖性溶血以预防急性视网膜神经变性


年龄相关性黄斑变性 (AMD) 是发达国家老年人失明的主要原因，预计到 2040 年，受影响的人数将几乎翻倍。视网膜是我们身体中代谢需求最高的区域之一，分别部分或完全由神经视网膜和视网膜色素上皮（RPE）中的线粒体完成。加上其有丝分裂后状态和来自入射光的持续光氧化损伤，视网膜需要一个严格调节的涉及自噬的管家系统。天然多酚尿石素 A (UA) 在多种衰老和年龄相关疾病模型中显示出神经保护作用，这主要归因于其诱导线粒体自噬和线粒体生物发生的能力。碘酸钠 (SI) 给药可重现 AMD 的晚期阶段，包括地图样萎缩和感光细胞死亡。结合体外、离体和体内模型来测试 UA 在 SI 模型中的神经保护潜力。功能测定（OCT、ERG）、细胞分析（流式细胞术、qPCR）和精细共聚焦显微镜（免疫组织化学、串联选择性自噬报告基因）有助于解决这个问题。 UA 可减轻 SI 治疗小鼠的神经退行性变并保留视觉功能。同时，我们观察到 SI 损伤诱导后出现严重的蛋白质稳态缺陷，包括自噬体积累，这些缺陷在接受 UA 的动物中得到了解决。如先前文献报道，UA 治疗可恢复自噬流并引发 PINK1/Parkin 依赖性线粒体自噬。 SI引起的自噬阻断是由严重的溶酶体膜透化引起的。 虽然UA不诱导溶酶体生物发生，但它确实通过溶食作用恢复了透化溶酶体的升级循环。在 SI 处理的细胞中，溶酶体接头 SQSTM1/p62 的敲除消除了 UA 的活力挽救，加剧了溶酶体缺陷并抑制了溶酶体。总的来说，这些数据强调了 UA 在治疗 AMD 中的一种新的推定应用，即它通过促进 p62 依赖性溶血作用来维持蛋白质稳态，从而绕过溶酶体缺陷。