Caspase-independent cell death and mitochondrial disruptions observed in the Apaf1-deficient cells
Caspase-independent cell death and mitochondrial disruptions observed in the Apaf1-deficient cells
复制标题
DOI：
10.1093/oxfordjournals.jbchem.a002944
复制
发表时间：
2001-06-01
影响因子：
2.7
通讯作者：
Nomoto, K
中科院分区：
文献类型：
--
作者：
Miyazaki, K;Yoshida, K;Nomoto, K
Apaf1是线粒体依赖的细胞凋亡途径中的关键分子。在这里，我们显示Apaf1缺陷的胚胎成纤维细胞在凋亡诱导的后期阶段死亡，尽管这些细胞在早期阶段对各种凋亡刺激物具有抵抗力。在Apaf1基因缺失的细胞死亡过程中，未见caspase 3激活或核固缩现象，电子显微镜检查显示，凋亡刺激引起的细胞死亡类似于坏死，细胞核呈圆形、肿胀，电子密度低。Z-VAD-fmk处理的野生型细胞也出现坏死样细胞死亡。线粒体不仅在形态上异常，而且在功能上也受到影响，因为即使在质膜完整的细胞中线粒体跨膜电位(Delta PSIM)也会丢失，这些线粒体变化也在死于凋亡的野生型细胞中观察到，这些数据表明，不激活caspase的细胞，如Apaf1基因缺陷的细胞或用caspase抑制剂处理的细胞，在“凋亡刺激”的反应下，死于坏死样细胞死亡并伴有线粒体损伤。
Apaf1 is a critical molecule in the mitochondria-dependent apoptotic pathway. Here we show that Apaf1-deficient embryonic fibroblasts died at a later phase of apoptotic induction, although these cells were resistant to various apoptotic stimulants at an early phase. Neither caspase 3 activation nor nuclear condensation was observed during this cell death of Apaf1-deficient cells, Electron microscopic examination revealed that death in response to apoptotic stimulation resembled necrosis ill that nuclei were round and swollen with low electron density. Necrosis-like cell death was also observed in wildtype cells treated with z-VAD-fmk. Mitochondria were not only morphologically abnormal but functionally affected, since mitochondrial transmembrane potential (Delta Psim) was lost even in cells with intact plasma membrane integrity, These mitochondrial alterations were also observed in the wild-type cells dying of apoptosis, Combined, these data suggest that cells without caspase activation, such as Apaf1-deficient cells or cells treated with caspase inhibitors, die of necrosis-like cell death with mitochondrial damage in response to "apoptotic stimulation."