中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (1): 89-90.doi: 10.4103/1673-5374.314300

• 观点:脊髓损伤修复保护与再生 • 上一篇    下一篇

铁死亡：铜铁诱导脱髓鞘过程中的铜铁连接

  

  • 出版日期:2022-01-05 发布日期:2021-09-18

Ferroptosis: copper-iron connection in cuprizone-induced demyelination

Priya Jhelum, Samuel David*   

  1. Centre for Research in Neuroscience and Brain Program, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
  • Online:2022-01-05 Published:2021-09-18
  • Contact: Samuel David, PhD, sam.david@mcgill.ca.
  • Supported by:
    The present work was supported by a grant from the Canadian Institutes of Health Research (CIHR) (MOP-142231) and MS Society of Canada (MSSOC) (to SD); and MSSOC postdoctoral fellowship (to PJ). 

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摘要：

Neural Regen Res：铁死亡在铜铁诱导少突胶质细胞丢失和脱髓鞘中的作用

    氧化还原活性金属如铁、铜、锌和锰在促进细胞功能所必需的各种生化反应中起着重要作用。这是因为这些金属能够接受和提供电子。以铁硫簇和血红素形式存在的铁在线粒体产生三磷酸腺苷以及许多其他酶反应中起着关键作用。这些金属的正常稳态水平的破坏，无论是过量还是减少，都会导致细胞和组织病理学的损伤。肝豆状核变性患者的中枢神经系统中铜的过量积累导致基底节损伤，而尖粒细胞增多症患者的中枢神经系统中铁的过量沉积导致大脑和视网膜的各个区域损伤。这种损伤被认为是由Fenton化学产生的自由基引起的。最近的研究揭示了铜铁是一种铜螯合剂，可诱导实验动物脱髓鞘，广泛用于研究中枢神经系统的脱髓鞘和再髓鞘化，通常用于多发性硬化症，即人类典型的脱髓鞘疾病。铁蛋白噬菌体在铁死亡中有潜在作用，即从胞浆铁蛋白释放铁。螯合铜能导致铁代谢失调。重要的是，铁死亡也可能在其他神经疾病中发挥作用，值得进一步研究。

     来自加拿大麦吉尔大学健康中心研究所的Samuel David团队认为中枢神经系统中的铁积聚发生在各种神经系统疾病中，因此可能对神经病理学有重要贡献。为了治疗这些疾病，铁螯合剂需要能够穿过血脑屏障，进入中枢神经系统的细胞，最后螯合剂-铁复合物需要从中枢神经系统中清除。还需要更好地了解铁介导细胞死亡的机制，因为这可能导致新的替代治疗方法。因此，在各种中枢神经系统疾病中鉴别和诊断铁死亡是一个重要的步骤。铁死亡可能发生在一些但不是所有伴有铁超载的神经系统疾病中。由于铁的积累在这些疾病中是慢性的，铁死亡可能只导致部分细胞毒性作用，并可能在疾病的不同阶段从急性到慢性有所不同。铁死亡也可能发生在没有明显铁积累（铁组织化学检测）的情况下，而是生物活性铁短暂增加，铁蛋白中铁储存减少，如铜试剂中毒。可用于测试脑脊液和活检样本的生物标志物以及神经系统疾病中的尸检材料的可用性将有助于做出此类确定，并为治疗铁介导的神经退行性变的更有效疗法铺平道路。

    文章在《中国神经再生研究（英文版）》杂志2022年 1 月 1 期发表。

https://orcid.org/0000-0002-3314-3695 (Samuel David) 

Abstract: Redox active metals such as iron, copper, zinc, and manganese play important roles in promoting a variety of biochemical reactions essential for cellular function. This is made possible by the ability of these metals to accept and donate electrons. Iron in the form of iron-sulfur clusters and heme plays a key role in adenosine triphosphate generation in mitochondria as well as numerous other enzymatic reactions. On the other hand, disruption in the normal homeostatic levels of these metals, either excess or reduction, results in damage to cells and to tissue pathology. Excess copper accumulation in the central nervous system (CNS) in Wilson’s disease results in damage to the basal ganglia, and excess iron deposition in the CNS in aceruloplasminemia results in damage to various regions of the brain and retina. Such damage is thought to be induced by free radicals generated via Fenton chemistry. Here, we focus on our recent work that revealed a role for ferroptosis, a form of iron-mediated cell death, in cuprizone-induced oligodendrocyte loss and demyelination (Jhelum et al., 2020). Cuprizone is a copper chelator that induces demyelination in experimental animals and is widely used to study demyelination and remyelination in the CNS (Zhan et al., 2020), often in the context of multiple sclerosis (MS), the prototypical demyelination disease in humans. Another key finding in this work is the potential role of ferritinophagy in ferroptosis, i.e., the release of iron from cytosolic ferritin (Dixon et al., 2012; Mancias et al., 2014). This work also shows the link between copper and iron metabolism, in which chelating copper leads to dysregulation of iron metabolism. Importantly, ferroptosis may also play a role in other neurological conditions and deserves further study.