Department of Ophthalmology & Visual Science, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China.
NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, and Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai 200031, China.
Molecules. 2022 Aug 4;27(15):4957. doi: 10.3390/molecules27154957.
Glutamate excitotoxicity may contribute to retinal ganglion cell (RGC) degeneration in glaucoma and other optic neuropathies, leading to irreversible blindness. Growing evidence has linked impaired mitochondrial quality control with RGCs degeneration, while parkin, an E3 ubiquitin ligase, has proved to be protective and promotes mitophagy in RGCs against excitotoxicity. The purpose of this study was to explore whether a small molecule S3 could modulate parkin-mediated mitophagy and has therapeutic potential for RGCs. The results showed that as an inhibitor of deubiquitinase USP30, S3 protected cultured RGCs and improved mitochondrial health against NMDA-induced excitotoxicity. Administration of S3 promoted the parkin expression and its downstream mitophagy-related proteins in RGCs. An upregulated ubiquitination level of Mfn2 and protein level of OPA1 were also observed in S3-treated RGCs, while parkin knockdown resulted in a major loss of the protective effect of S3 on RGCs under excitotoxicity. These findings demonstrated that S3 promoted RGC survival mainly through enhancing parkin-mediated mitophagy against excitotoxicity. The neuroprotective value of S3 in glaucoma and other optic neuropathies deserves further investigation.
谷氨酸兴奋性毒性可能导致青光眼和其他视神经病变中的视网膜神经节细胞 (RGC) 变性，导致不可逆转的失明。越来越多的证据表明，受损的线粒体质量控制与 RGC 变性有关，而 parkin（一种 E3 泛素连接酶）已被证明具有保护作用，并促进 RGC 对兴奋性毒性的线粒体自噬。本研究旨在探讨小分子 S3 是否可以调节 parkin 介导的线粒体自噬，并具有治疗 RGC 的潜力。结果表明，作为去泛素酶 USP30 的抑制剂，S3 可保护培养的 RGC 并改善其线粒体健康，防止 NMDA 诱导的兴奋性毒性。S3 处理可促进 RGC 中 parkin 的表达及其下游与线粒体自噬相关的蛋白。在 S3 处理的 RGC 中，Mfn2 的泛素化水平和 OPA1 的蛋白水平也上调，而 parkin 敲低会导致 S3 在兴奋性毒性下对 RGC 的保护作用大大丧失。这些发现表明，S3 主要通过增强 parkin 介导的线粒体自噬来促进 RGC 的存活，以对抗兴奋性毒性。S3 在青光眼和其他视神经病变中的神经保护价值值得进一步研究。
