Ferritin confers protection against iron-mediated neurotoxicity and ferroptosis through iron chelating mechanisms in MPP+-induced MES23.5 dopaminergic cells
Ferritin confers protection against iron-mediated neurotoxicity and ferroptosis through iron chelating mechanisms in MPP+-induced MES23.5 dopaminergic cells
复制标题
铁蛋白通过 MPP 诱导的 MES23.5 多巴胺能细胞中的铁螯合机制提供针对铁介导的神经毒性和铁死亡的保护
DOI：
10.1016/j.freeradbiomed.2022.11.018
复制
发表时间：
2022-11-21
影响因子：
7.4
通讯作者：
Xu，Huamin
中科院分区：
文献类型：
--
作者：
Zhang，Na;Yu，Xiaoqi;Xu，Huamin
铁蛋白是主要的铁储存蛋白，在维持铁稳态中起重要作用。在以前的研究中，我们报道了去铁蛋白通过调节脑铁代谢和铁凋亡对MPTP产生神经保护作用。然而，这种保护作用背后的细胞外铁蛋白的确切细胞机制尚未完全阐明。据报道，铁蛋白定位于不同的细胞内区室、细胞质或释放到细胞外。在这里，我们证明了在原代培养的星形胶质细胞中，铁处理后细胞内铁增加。这些负载铁的星形胶质细胞释放更多的铁蛋白，以缓冲细胞外铁。利用原代培养的星形胶质细胞与MES 23.5多巴胺能细胞共培养体系，我们发现星形胶质细胞释放的铁蛋白可以进入MES 23.5多巴胺能细胞。原代培养的星形胶质细胞对1-甲基-4-苯基吡啶离子（MPP+）诱导的多巴胺能细胞毒性和铁凋亡具有保护作用。此外，我们发现外源性脱铁铁蛋白或铁蛋白预处理可以显著抑制MPP+诱导的细胞损伤，恢复细胞活力和线粒体跨膜电位。此外，外源性脱铁铁蛋白和铁蛋白还可能通过减少活性氧（ROS）和抑制不稳定铁库（LIP）的增加而保护MES 23.5多巴胺能细胞免受MPP+的损伤。这表明星形胶质细胞增加铁蛋白释放以响应铁过载，这可能抑制帕金森病（PD）中铁介导的多巴胺（DA）神经元的氧化损伤和铁凋亡。
Ferritin is the main iron storage protein and plays an important role in maintaining iron homeostasis. In a previous study, we reported that apoferritin exerted a neuroprotective effect against MPTP by regulation of brain iron metabolism and ferroptosis. However, the precise cellular mechanisms of extracellular ferritin underlying this protection are not fully elucidated. Ferritin was reported to be localized in different intracellular compartments, cytoplasm or released outside cells. Here we demonstrated that the intracellular iron increased after iron treatment in primary cultured astrocytes. These iron-loaded astrocytes released more ferritin in order to buffer extracellular iron. Using co-culture system of primary cultured astrocytes and MES23.5 dopaminergic cells, we showed that ferritin released by astrocytes could enter MES23.5 dopaminergic cells. And primary cultured astrocytes protected MES23.5 dopaminergic cells against 1-methyl-4-phenylpyridinium ion (MPP+)-induced neurotoxicity and ferroptosis. In addition, we found that exogenous Apoferritin or Ferritin pretreatment could significantly inhibit MPP+-induced cell damage by restoring the cell viability and mitochondrial transmembrane potential (ΔΨm). Furthermore, exogenous Apoferritin and Ferritin might also protect MES23.5 dopaminergic cells against MPP+by decreasing reactive oxygen species (ROS) and inhibiting the increase of the labile iron pool (LIP). This suggests that astrocytes increased ferritin release to respond to iron overload, which might inhibit iron-mediated oxidative damage and ferroptosis of dopamine (DA) neurons in Parkinson's disease (PD).