The exceptional sensitivity of brain mitochondria to copper
The exceptional sensitivity of brain mitochondria to copper
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DOI：
10.1016/j.tiv.2018.04.012
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发表时间：
2018-09-01
影响因子：
3.2
通讯作者：
Zischka, Hans
中科院分区：
文献类型：
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作者：
Borchard, Sabine;Bork, Francesca;Zischka, Hans
肝豆状核变性（WD）的特征是铜稳态被破坏，导致铜水平急剧升高，主要在肝脏和大脑中。虽然铜对线粒体的损伤是WD肝脏的既定特征，但对其他器官中的这种有害铜效应知之甚少。因此，我们评估了组织特异性的方式，即离体大鼠肝，肾，心脏和脑线粒体的线粒体对铜的敏感性。脑线粒体呈现出异常的铜敏感性，如通过相对早期的膜电位损失、在低铜剂量下已经发生的深刻的结构变化以及产生ATP的能力的剂量依赖性降低所证明的。这种敏感性可能是由于对游离蛋白硫醇的铜依赖性攻击以及由于铜反应性防御系统降低，如在神经母细胞瘤SHSY5Y细胞中进一步证明的。相比之下，活性氧的产生增加被认为是一个晚期事件，只发生在被破坏的线粒体。因此，我们建议线粒体蛋白硫醇作为线粒体铜毒性的主要目标。
Wilson disease (WD) is characterized by a disrupted copper homeostasis resulting in dramatically increased copper levels, mainly in liver and brain. While copper damage to mitochondria is an established feature in WD livers, much less is known about such detrimental copper effects in other organs. We therefore assessed the mitochondrial sensitivity to copper in a tissue specific manner, namely of isolated rat liver, kidney, heart, and brain mitochondria. Brain mitochondria presented with exceptional copper sensitivity, as evidenced by a comparatively early membrane potential loss, profound structural changes already at low copper dose, and a dose-dependent reduced capacity to produce ATP. This sensitivity was likely due to a copper-dependent attack on free protein thiols and due to a decreased copper reactive defense system, as further evidenced in neuroblastoma SHSY5Y cells. In contrast, an increased production of reactive oxygen species was found to be a latestage event, only occurring in destroyed mitochondria. We therefore propose mitochondrial protein thiols as major targets of mitochondrial copper toxicity.