Ferroptosis drives photoreceptor degeneration in mice with defects in all-trans-retinal clearance.
Ferroptosis drives photoreceptor degeneration in mice with defects in all-trans-retinal clearance.
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铁死亡导致全视网膜间隙缺陷小鼠的光感受器变性
DOI：
10.1074/jbc.ra120.015779
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Wu Y
中科院分区：
文献类型：
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作者：
Chen C;Chen J;Wang Y;Liu Z;Wu Y
干性年龄相关性黄斑变性（AMD）和常染色体隐性Stargardt病（STGD1）的光感受器细胞死亡与神经视网膜全反式视网膜（atRAL）清除的中断密切相关。在这项研究中，我们揭示了atRAL过载通过激活铁下垂（一种非凋亡的细胞死亡形式）导致光感受器变性。atRAL诱导的光感受器细胞凋亡是由铁离子（Fe2+）增加、ACSL4表达升高、系统Xc−抑制和线粒体破坏引起的。铁离子过载、三肽谷胱甘肽（GSH）耗竭和暴露于atRAL的光受体细胞线粒体损伤引起活性氧（ROS）的产生，与ACSL4激活一起促进脂质过氧化，从而引起铁致细胞死亡。此外，光感受器细胞暴露于atRAL激活COX2，这是一种公认的铁下垂发病的生物标志物。除了补充谷胱甘肽外，通过甲磺酸去铁胺盐（DFO）或他汀铁素-1 （Fer-1）的脂质过氧化抑制Fe2+可以保护光感受器细胞免受atRAL引起的铁凋亡。Abca4−/−Rdh8−/−小鼠的atRAL清除缺陷是干性AMD和STGD1的动物模型。我们观察到光照后Abca4−/−Rdh8−/−小鼠的神经视网膜确实存在铁下垂。更重要的是，通过腹腔注射选择性铁下垂抑制剂Fer-1，可以有效减轻光暴露的Abca4−/−Rdh8−/−小鼠的光感受器萎缩和铁下垂。我们的研究表明，铁下垂是视网膜病变中光感受器细胞死亡的重要途径之一，应作为预防干性AMD和STGD1的新靶点。
The death of photoreceptor cells in dry age-related macular degeneration (AMD) and autosomal recessive Stargardt disease (STGD1) is closely associated with disruption in all-trans-retinal (atRAL) clearance in neural retina. In this study, we reveal that the overload of atRAL leads to photoreceptor degeneration through activating ferroptosis, a nonapoptotic form of cell death. Ferroptosis of photoreceptor cells induced by atRAL resulted from increased ferrous ion (Fe2+), elevated ACSL4 expression, system Xc− inhibition, and mitochondrial destruction. Fe2+ overload, tripeptide glutathione (GSH) depletion, and damaged mitochondria in photoreceptor cells exposed to atRAL provoked reactive oxygen species (ROS) production, which, together with ACSL4 activation, promoted lipid peroxidation and thereby evoked ferroptotic cell death. Moreover, exposure of photoreceptor cells to atRAL activated COX2, a well-accepted biomarker for ferroptosis onset. In addition to GSH supplement, inhibiting either Fe2+ by deferoxamine mesylate salt (DFO) or lipid peroxidation with ferrostatin-1 (Fer-1) protected photoreceptor cells from ferroptosis caused by atRAL. Abca4−/−Rdh8−/− mice exhibiting defects in atRAL clearance is an animal model for dry AMD and STGD1. We observed that ferroptosis was indeed present in neural retina of Abca4−/−Rdh8−/− mice after light exposure. More importantly, photoreceptor atrophy and ferroptosis in light-exposed Abca4−/−Rdh8−/− mice were effectively alleviated by intraperitoneally injected Fer-1, a selective inhibitor of ferroptosis. Our study suggests that ferroptosis is one of the important pathways of photoreceptor cell death in retinopathies arising from excess atRAL accumulation and should be pursued as a novel target for protection against dry AMD and STGD1.