Zn2+ induces permeability transition pore opening and release of pro-apoptotic peptides from neuronal mitochondria
Zn2+ induces permeability transition pore opening and release of pro-apoptotic peptides from neuronal mitochondria
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DOI：
10.1074/jbc.m108834200
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发表时间：
2001-12-14
影响因子：
4.8
通讯作者：
Weiss, JH
中科院分区：
文献类型：
--
作者：
Jiang, DM;Sullivan, PG;Weiss, JH
Ca2+ 或 Zn2+ 的快速进入会杀死神经元。线粒体是 Ca2+ 依赖性毒性的主要部位。本研究检查了 Zn2+ 引发的线粒体细胞死亡信号传导。 10 nm Zn2+ 诱导分离线粒体急性肿胀，其程度远大于较高 Ca2+ 水平诱导的肿胀。 Zn2+ 进入线粒体依赖于 Ca2+ 单向转运蛋白，随后的肿胀是由于线粒体通透性转换孔的打开造成的。完整神经元的共聚焦成像显示，Zn2+（与 Ca2+）的进入导致明显的线粒体肿胀，其程度远远大于单独 Ca2+ 进入引起的肿胀。进一步的实验比较了 Zn2+ 和 Ca2+ 诱导线粒体释放细胞色素 c (Cyt-c) 或凋亡诱导因子的能力。在分离的线粒体中，10 nm Zn2+ 暴露诱导 Cyt-c 释放。诱导 Zn2+ 进入皮质神经元，导致 60 分钟内胞质 Cyt-c 免疫标记以及胞质和核凋亡诱导因子标记明显增加。相比之下，较高的绝对 [Ca2+](i) 升高在诱导这些因子的释放方面效果较差。暴露后 5-6 小时通过台盼蓝染色评估，添加线粒体通透性转换孔抑制剂环孢菌素 A 和 bongkrekic 酸减少了 Zn2+ 依赖性因子的释放，并减弱了神经元细胞死亡。
Rapid entry of Ca2+ or Zn2+ kills neurons. Mitochondria are major sites of Ca2+-dependent toxicity. This study examines Zn2+-initiated mitochondrial cell death signaling. 10 nm Zn2+ induced acute swelling of isolated mitochondria, which was much greater than that induced by higher Ca2+ levels. Zn2+ entry into mitochondria was dependent upon the Ca2+ uniporter, and the consequent swelling resulted from opening of the mitochondrial permeability transition pore. Confocal imaging of intact neurons revealed entry of Zn2+ (with Ca2+) to cause pronounced mitochondrial swelling, which was far greater than that induced by Ca2+ entry alone. Further experiments compared the abilities of Zn2+ and Ca2+ to induce mitochondrial release of cytochrome c (Cyt-c) or apoptosis-inducing factor. In isolated mitochondria, 10 nm Zn2+ exposures induced Cyt-c release. Induction of Zn2+ entry into cortical neurons resulted in distinct increases in cytosolic Cyt-c immunolabeling and in cytosolic and nuclear apoptosis-inducing factor labeling within 60 min. In comparison, higher absolute [Ca2+](i) rises were less effective in inducing release of these factors. Addition of the mitochondrial permeability transition pore inhibitors cyclosporin A and bongkrekic acid decreased Zn2+-dependent release of the factors and attenuated neuronal cell death as assessed by trypan blue staining 5-6 h after the exposures.