Up‐regulation of divalent metal transporter 1 is involved in 1‐methyl‐4‐phenylpyridinium (MPP+)‐induced apoptosis in MES23.5 cells
Up‐regulation of divalent metal transporter 1 is involved in 1‐methyl‐4‐phenylpyridinium (MPP+)‐induced apoptosis in MES23.5 cells
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DOI：
10.1016/j.cellbi.2008.01.057
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发表时间：
2008-03
影响因子：
3.9
通讯作者：
Shu Zhen Zhang;Jun Wang;N. Song;Junxia Xie;Hong Jiang
中科院分区：
文献类型：
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作者：
Shu Zhen Zhang;Jun Wang;N. Song;Junxia Xie;Hong Jiang
细胞凋亡已被确定为参与帕金森病（PD）多巴胺能神经元变性的重要机制之一。我们以前的研究表明，在1-甲基-4-苯基-1，2，3，6-四氢吡啶诱导的PD小鼠模型中，黑质铁水平增加，多巴胺能神经元丢失。1-甲基-4-苯基吡啶鎓（MPP+）通常用于建立PD的细胞模型。虽然细胞内铁在MPP+诱导的细胞凋亡中起着至关重要的作用，但铁增加和MPP+诱导的神经变性的分子机制在很大程度上是未知的。在本研究中，我们调查的参与二价金属转运蛋白1（DMT 1）占二价铁运输MPP+处理的MES 23.5细胞。在经处理的细胞中，观察到亚铁的显著流入。这导致线粒体膜电位降低。此外，还检测到ROS产生水平升高和caspase-3活化，以及随后的细胞凋亡。铁螯合剂去铁醛（DFO）可完全消除这些作用。DMT 1（−IRE）表达增加而不是DMT 1（+IRE）表达增加是铁内流增加的原因。然而，有铁调节蛋白1（IRP 1）的变化，尽管IRP 2的表达减少。铁本身对IRP 1和IRP 2的表达没有影响。我们的数据表明，尽管DMT 1 mRNA含有铁响应元件，但其表达并不完全受其控制。MPP+以非IRE/IRP依赖的方式上调DMT 1（−IRE）的表达。我们的研究结果还表明，MPP+诱导的细胞凋亡在MES23.5涉及DMT 1依赖的铁内流和线粒体功能障碍。
Apoptosis has been identified as one of the important mechanisms involved in the degeneration of dopaminergic neurons in Parkinson's disease (PD). Our previous study showed increased iron levels in the substantia nigra as well as loss of dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mouse models. 1-Methyl-4-phenylpyridinium (MPP+) is commonly used to establish a cellular model of PD. Although intracellular iron plays a crucial role in MPP+-induced apoptosis, the molecular mechanism linking increased iron and MPP+-induced neurodegeneration is largely unknown. In the present study, we investigate the involvement of divalent metal transporter 1 (DMT1) that accounts for the ferrous iron transport in MPP+-treated MES23.5 cells. In the treated cells, a significant influx of ferrous iron was observed. This resulted in a decreased mitochondrial membrane potential. Additionally, an elevated level of ROS production and activation of caspase-3 were also detected, as well as the subsequent cell apoptosis. These effects could be fully abolished by using iron chelator desferal (DFO). Increased DMT1 (−IRE) expression but not DMT1 (+IRE) accounted for the increased iron influx. However, there were no changes for iron regulatory protein 1 (IRP1), despite decreased expression of IRP2. Iron itself had no effect on IRP1 and IRP2 expression. Our data suggest that although DMT1 mRNA contains an iron responsive element, its expression is not totally controlled by this. MPP+could up-regulate the expression of DMT1 (−IRE) in an IRE/IRP-independent manner. Our findings also show that MPP+-induced apoptosis in MES23.5 cells involves DMT1-dependent iron influx and mitochondria dysfunction.