DRP1-dependent apoptotic mitochondrial fission occurs independently of SAX, BAK and APAF1 to amplify cell death by BID and oxidative stress
DRP1-dependent apoptotic mitochondrial fission occurs independently of SAX, BAK and APAF1 to amplify cell death by BID and oxidative stress
复制标题
DOI：
10.1016/j.bbabio.2016.03.016
复制
发表时间：
2016-08-01
影响因子：
4.3
通讯作者：
Scorrano, Luca
中科院分区：
文献类型：
--
作者：
Oettinghaus, Bjorn;D'Alonzo, Donato;Scorrano, Luca
在细胞凋亡过程中，线粒体经历嵴重构和断裂，但后者与外膜渗透和下游半胱天冬酶活化的关系尚不清楚。在这里，我们表明线粒体裂变蛋白动力蛋白相关蛋白（Drp） 1参与细胞色素c释放的选择内在死亡刺激。Bax、Bak双缺陷（DKO）和Apafl（-1-）小鼠胚胎成纤维细胞（mef）受Bcl-2家族成员BID、H2O2、staurosporine和thapsigargin的影响较小，而Drp1(-/-) mef仅受BID和H2O2的保护。Drp1（-/-）和DKO MEFs对细胞死亡的抗性与细胞色素c释放减弱相关，而所有细胞系在对所有测试刺激的反应中都发生了线粒体断裂，这表明其他机制可以解释细胞色素c释放减少。事实上，Drpl（-/-）细胞的嵴重塑减少，这可能解释了它们对凋亡的抵抗。我们的研究结果表明，不依赖caspase的线粒体分裂和依赖drp1的嵴重塑会放大细胞凋亡。这篇文章是题为“EBEC 2016：第19届欧洲生物能量学会议，Riva del Garda，意大利，7月2日至6日，2016”特刊的一部分，由Paolo Bernardi教授编辑。(C) 2016 Elsevier B.V.版权所有
During apoptosis mitochondria undergo cristae remodeling and fragmentation, but how the latter relates to outer membrane permeabilization and downstream caspase activation is unclear. Here we show that the mitochondrial fission protein Dynamin Related Protein (Drp) 1 participates in cytochrome c release by selected intrinsic death stimuli. While Bax, Bak double deficient (DKO) and Apafl(-1-) mouse embryonic fibroblasts (MEFs) were less susceptible to apoptosis by Bcl-2 family member BID, H2O2, staurosporine and thapsigargin, Drp1(-/-) MEFs were protected only from BID and H2O2. Resistance to cell death of Drp1(-/-) and DKO MEFs correlated with blunted cytochrome c release, whereas mitochondrial fragmentation occurred in all cell lines in response to all tested stimuli, indicating that other mechanisms accounted for the reduced cytochrome c release. Indeed, cristae remodeling was reduced in Drpl(-/-) cells, potentially explaining their resistance to apoptosis. Our results indicate that caspase-independent mitochondrial fission and Drp1-dependent cristae remodeling amplify apoptosis. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi. (C) 2016 Elsevier B.V. All rights reserved.