Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs
Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs
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DOI：
10.1038/sj.emboj.7601975
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发表时间：
2008-01-23
期刊：
影响因子：
11.4
通讯作者：
Nakabeppu, Yusaku
中科院分区：
文献类型：
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作者：
Oka, Sugako;Ohno, Mizuki;Nakabeppu, Yusaku
氧化性碱基损伤，如8-氧代鸟嘌呤（8-oxoG），在氧化应激下在细胞核和线粒体DNA中积累，导致细胞死亡。然而，目前还不知道涉及哪种形式的DNA，是细胞核还是线粒体，也不知道死亡命令是如何执行的。我们通过在OGG 1缺失的小鼠细胞中表达核或线粒体形式的人8-oxoG DNA糖基化酶，建立了选择性地在任一类型的DNA中积累8-oxoG的细胞。8-oxoG在核DNA中的积累引起聚ADP-核糖聚合酶（PARP）依赖的凋亡诱导因子的核转位，而在线粒体DNA中的积累引起线粒体功能障碍和Ca 2+释放，从而激活钙蛋白酶。两种细胞死亡都是由在各自DNA中积累的单链断裂（SSB）触发的，并且通过MutY同源物编码的腺嘌呤DNA糖基化酶的敲低而被抑制，因此表明与8-oxoG相对的腺嘌呤的切除导致SSB在每种类型的DNA中积累。核DNA中的SSB激活PARP，而线粒体DNA中的SSB导致其耗尽，从而启动两种不同的细胞死亡途径。
Oxidative base lesions, such as 8-oxoguanine ( 8-oxoG), accumulate in nuclear and mitochondrial DNAs under oxidative stress, resulting in cell death. However, it is not known which form of DNA is involved, whether nuclear or mitochondrial, nor is it known how the death order is executed. We established cells which selectively accumulate 8-oxoG in either type of DNA by expression of a nuclear or mitochondrial form of human 8-oxoG DNA glycosylase in OGG1-null mouse cells. The accumulation of 8-oxoG in nuclear DNA caused poly-ADP-ribose polymerase ( PARP)-dependent nuclear translocation of apoptosis-inducing factor, whereas that in mitochondrial DNA caused mitochondrial dysfunction and Ca2+ release, thereby activating calpain. Both cell deaths were triggered by single-strand breaks ( SSBs) that had accumulated in the respective DNAs, and were suppressed by knockdown of adenine DNA glycosylase encoded by MutY homolog, thus indicating that excision of adenine opposite 8-oxoG lead to the accumulation of SSBs in each type of DNA. SSBs in nuclear DNA activated PARP, whereas those in mitochondrial DNA caused their depletion, thereby initiating the two distinct pathways of cell death.