Cardiolipin deficiency leads to decreased cardiolipin peroxidation and increased resistance of cells to apoptosis
Cardiolipin deficiency leads to decreased cardiolipin peroxidation and increased resistance of cells to apoptosis
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DOI：
10.1016/j.freeradbiomed.2008.02.016
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发表时间：
2008-06-01
影响因子：
7.4
通讯作者：
Kagan, Valerian E.
中科院分区：
文献类型：
--
作者：
Huang, Zhentai;Jiang, Jianfei;Kagan, Valerian E.
心磷脂（CL）是由心磷脂合成酶（CL synthase，CLS）合成的一种独特的线粒体磷脂，在细胞凋亡中起重要作用，但尚未完全了解。我们操纵CL HeLa细胞中的水平，通过敲低CLS使用RNA干扰，并选择了一个克隆的CL缺陷细胞与其正常含量的45%相似。ESI-MS分析表明，CL缺乏和CL充足的细胞中CL分子种类相同。CL缺乏不改变线粒体功能（膜电位、活性氧生成、细胞ATP水平），但赋予对放线菌素D（Act[D]）、鱼藤酮或γ-辐射诱导的细胞凋亡的抗性。ActD诱导的细胞凋亡过程中，CL过氧化反应降低沿着细胞色素（cyt）c的释放被抑制，观察到在CL-缺陷的细胞，而Bax易位到线粒体仍然类似于CL-足够的HeLa细胞。松散结合的细胞色素c（在高离子强度条件下可释放）的量在CL-缺乏和CL-充足的细胞中是相同的。鉴于CL过氧化在细胞凋亡过程中是由CL/细胞色素c复合物催化和CL氧化产物是必不可少的细胞色素c从线粒体释放，我们的研究结果表明，CL缺乏阻止生产CL/细胞色素c复合物和CL过氧化充分组装，导致抗凋亡。(C)2008年爱思唯尔公司All rights reserved.
Cardiolipin (CL), a unique mitochondrial phospholipid synthesized by CL synthase (CLS), plays important, yet not fully understood, roles in mitochondria-dependent apoptosis. We manipulated CL levels in HeLa cells by knocking down CLS using RNA interference and selected a clone of CL-deficient cells with similar to 45% of its normal content. ESI-MS analysis showed that the CL molecular species were the same in CL-deficient and CL-sufficient cells. CL deficiency did not change mitochondrial functions (membrane potential, reactive oxygen species generation, cellular ATP levels) but conferred resistance to apoptosis induced by actinomycin D (Act[D), rotenone, or gamma-irradiation. During ActD-induced apoptosis, decreased CL peroxidation along with suppressed cytochrome (cyt) c release was observed in CL-deficient cells, whereas Bax translocation to mitochondria remained similar to that in CL-sufficient HeLa cells. The amounts of loosely bound cyt c (releasable under high ionic strength conditions) were the same in CL-deficient and CL-sufficient cells. Given that CL peroxidation during apoptosis is catalyzed by CL/cyt c complexes and CL oxidation products are essential for cyt c release from mitochondria, our results suggest that CL deficiency prevents adequate assembly of productive CL/cyt c complexes and CL peroxidation, resulting in increased resistance to apoptosis. (C) 2008 Elsevier Inc. All rights reserved.