Minimal effect of conditional ferroportin KO in the neural retina implicates ferrous iron in retinal iron overload and degeneration.
Minimal effect of conditional ferroportin KO in the neural retina implicates ferrous iron in retinal iron overload and degeneration.
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DOI：
10.1016/j.exer.2022.108988
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发表时间：
2022-05
影响因子：
3.4
通讯作者：
Dunaief, Joshua L.
中科院分区：
文献类型：
--
作者：
Liu, Yingrui;Baumann, Bailey;Song, Ying;Zhang, Kevin;Sterling, Jacob K.;Lakhal-Littleton, Samira;Kozmik, Zbynek;Su, Guanfang;Dunaief, Joshua L.
铁诱导的氧化应激可导致或加剧视网膜退行性疾病。已经报道了几种视网膜铁超载的小鼠疾病模型，这些小鼠的视网膜同源铁氧化酶铜蓝蛋白(Cp)和肝磷脂(Hephestn)被全身性或神经性视网膜特异性敲除(KO)。CP和HEPH可增强铁门蛋白(FPN)介导的细胞铁输出。在这里，我们使用视网膜特异的FPN KO小鼠来验证CP/Heph DKO小鼠的视网膜铁超载是由神经元和神经胶质细胞铁输出受损引起的假说。令人惊讶的是，没有迹象表明视网膜特异性FPN KO小鼠的视网膜铁超载：在7-10个月大的时候，视网膜中转铁蛋白受体的mRNA水平没有改变。与此一致的是，铁蛋白轻链的水平和定位没有变化。为了“对系统施加压力”，我们向患有或不患有CPKO的FPN KO小鼠腹膜内注射铁。只有同时患有视网膜特异性FPN KO和CP KO的小鼠的视网膜铁水平略有升高。这些结果表明，通过FPN的铁输出受损不足以解释CP/Heph DKO小鼠视网膜铁超载的原因。由于缺乏这些铁氧合酶而导致的视网膜亚铁水平的增加，随后亚铁进口商对细胞的摄取，这很可能是必要的。
Iron-induced oxidative stress can cause or exacerbate retinal degenerative diseases. Retinal iron overload has been reported in several mouse disease models with systemic or neural retina-specific knockout (KO) of homologous ferroxidases ceruloplasmin (Cp) and hephaestin (Heph). Cp and Heph can potentiate ferroportin (Fpn) mediated cellular iron export. Here, we used retina-specific Fpn KO mice to test the hypothesis that retinal iron overload in Cp/Heph DKO mice is caused by impaired iron export from neurons and glia. Surprisingly, there was no indication of retinal iron overload in retina-specific Fpn KO mice: the mRNA levels of transferrin receptor in the retina were not altered at 7–10-months age. Consistent with this, levels and localization of ferritin light chain were unchanged. To “stress the system”, we injected iron intraperitoneally into Fpn KO mice with or without Cp KO. Only mice with both retina-specific Fpn KO and Cp KO had modestly elevated retinal iron levels. These results suggest that impaired iron export through Fpn is not sufficient to explain the retinal iron overload in Cp/Heph DKO mice. An increase in the levels of retinal ferrous iron caused by the absence of these ferroxidases, followed by uptake into cells by ferrous iron importers, is most likely necessary.
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影响因子：
29
作者：
Donovan, A;Lima, CA;Andrews, NC
通讯作者：
Andrews, NC
影响因子：
4.4
作者：
Dunaief, Joshua L.
通讯作者：
Dunaief, Joshua L.
影响因子：
4.4
作者：
Hadziahmetovic, Majda;Song, Ying;Dunaief, Joshua L.
通讯作者：
Dunaief, Joshua L.
影响因子：
4.2
作者：
BURCH, PG;ALBERT, DM
通讯作者：
ALBERT, DM
影响因子：
4.8
作者：
Theurl, Milan;Song, Delu;Dunaief, Joshua L.
通讯作者：
Dunaief, Joshua L.