Iron is an essential element for cellular functions, including those of neuronal cells. However, an imbalance of iron homeostasis, such as iron overload, has been observed in several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Iron overload causes neuronal toxicity through mitochondrial fission, dysregulation of Ca2+, ER-stress, and ROS production. Nevertheless, the precise mechanisms between iron-induced oxidative stress and iron toxicity related to mitochondria and endoplasmic reticulum (ER) in vivo are not fully understood. Here, we demonstrate the role of peroxiredoxin 5 (Prx5) in iron overload-induced neurotoxicity using Prx5-deficient mice. Iron concentrations and ROS levels in mice fed a high iron diet were significantly higher in Prx5-/- mice than wildtype (WT) mice. Prx5 deficiency also exacerbated ER-stress and ER-mediated mitochondrial fission via Ca2+/calcineurin-mediated dephosphorylation of Drp1 at Serine 637. Moreover, immunoreactive levels of cleaved caspase3 in the CA3 region of the hippocampus were higher in iron-loaded Prx5-/- mice than WT mice. Furthermore, treatment with N-acetyl-cysteine, a reactive oxygen species (ROS) scavenger, attenuated iron overload-induced hippocampal damage by inhibiting ROS production, ER-stress, and mitochondrial fission in iron-loaded Prx5-/- mice. Therefore, we suggest that iron overload-induced oxidative stress and ER-mediated mitochondrial fission may be essential for understanding iron-mediated neuronal cell death in the hippocampus and that Prx5 may be useful as a novel therapeutic target in the treatment of iron overload-mediated diseases and neurodegenerative diseases.

中文翻译：

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Peroxiredoxin 5缺乏症通过ER介导的小鼠海马线粒体裂变加剧了铁超负荷诱导的神经元死亡。

铁是包括神经元细胞在内的细胞功能所必需的元素。然而，在包括阿尔茨海默氏病和帕金森氏病在内的几种神经退行性疾病中已经观察到铁稳态的失衡，例如铁超负荷。铁超负荷通过线粒体裂变，Ca2 +失调，ER应激和ROS产生引起神经元毒性。然而，在体内铁与线粒体和内质网（ER）有关的氧化应激和铁毒性之间的确切机制尚不完全清楚。在这里，我们证明过氧化物酶5（Prx5）在使用Prx5缺陷小鼠的铁超负荷诱导的神经毒性中的作用。喂高铁饮食的小鼠中的铁浓度和ROS水平在Prx5-/-小鼠中显着高于野生型（WT）小鼠。Prx5缺乏症还通过Ca2 + /钙调神经磷酸酶介导的Serp 637上Drp1的去磷酸化作用加剧了ER应激和ER介导的线粒体裂变。此外，铁负载的Prx5-/-中海马CA3区裂解的caspase3的免疫反应水平更高。小鼠比野生型小鼠。此外，用N-乙酰半胱氨酸（一种活性氧清除剂）处理，可通过抑制铁负载的Prx5-/-小鼠中的ROS产生，内质网应激和线粒体裂变，减轻铁过载引起的海马损伤。因此，