Mechanism of cell death caused by complex I defects in a rat dopaminergic cell line
Mechanism of cell death caused by complex I defects in a rat dopaminergic cell line
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DOI：
10.1074/jbc.m701819200
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发表时间：
2007-08-17
影响因子：
4.8
通讯作者：
Yagi, Takao
中科院分区：
文献类型：
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作者：
Marella, Mathieu;Seo, Byoung Boo;Yagi, Takao
哺乳动物线粒体质子转运NADH-醌氧化还原酶（复合物I）的缺陷与神经退行性疾病有关.复合物I缺乏引起细胞死亡的机制仍然难以捉摸。我们已经表明，鱼藤酮不敏感的酵母NADH醌氧化还原酶（Ndi 1）的表达可以拯救哺乳动物细胞从复合物I功能障碍。通过使用Ndi 1酶，我们研究了使用大鼠多巴胺能细胞系PC 12的细胞死亡过程中的关键事件。我们发现复合物I抑制引起以下事件：1）特定激酶途径的激活; 2）线粒体促凋亡因子、凋亡诱导因子和核酸内切酶G的释放。激酶抑制剂AS 601245对这些凋亡事件表现出显著的保护作用。传统的半胱天冬酶途径似乎不参与，因为没有观察到半胱天冬酶3激活。我们的数据表明，由复合物I抑制引起的活性氧（ROS）的过度产生负责触发激酶激活，释放促凋亡因子，然后导致细胞死亡。Ndi 1对凋亡性细胞死亡的几乎完美的预防与我们早期的观察一致，即Ndi 1的存在减少了鱼藤酮诱导的复合物I的ROS产生。事实上，这项研究表明，Ndi 1保持氧化还原电位高，即使在鱼藤酮的存在下。在这些条件下，已知由复合物I形成的ROS是最小的。我们的细胞模型的可能用途进行了讨论，关于复杂的I缺陷引起的神经退行性疾病的治疗策略的发展。
Defects in the proton- translocating NADH- quinone oxidoreductase (complex I) of mammalian mitochondria are linked to neurodegenerative disorders. The mechanism leading to cell death elicited by complex I deficiency remains elusive. We have shown that expression of a rotenone- insensitive yeast NADHquinone oxidoreductase ( Ndi1) can rescue mammalian cells from complex I dysfunction. By using the Ndi1 enzyme, we have investigated the key events in the process of cell death using a rat dopaminergic cell line, PC12. We found that complex I inhibition provokes the following events: 1) activation of specific kinase pathways; 2) release of mitochondrial proapoptotic factors, apoptosis inducing factor, and endonuclease G. AS601245, a kinase inhibitor, exhibited significant protection against these apoptotic events. The traditional caspase pathway does not seems to be involved because caspase 3 activation was not observed. Our data suggest that overproduction of reactive oxygen species ( ROS) caused by complex I inhibition is responsible for triggering the kinase activation, for the release of the proapoptotic factors, and then for cell death. Nearly perfect prevention of apoptotic cell death by Ndi1 agrees with our earlier observation that the presence of Ndi1 diminishes rotenone- induced ROS generation from complex I. In fact, this study demonstrated that Ndi1 keeps the redox potential high even in the presence of rotenone. Under these conditions, ROS formation by complex I is known to be minimal. Possible use of our cellular model is discussed with regard to development of therapeutic strategies for neurodegenerative diseases caused by complex I defects.