Mitochondrial dynamics following global cerebral ischemia.
Mitochondrial dynamics following global cerebral ischemia.
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DOI：
10.1016/j.mcn.2016.08.010
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发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Sanderson TH
中科院分区：
文献类型：
--
作者：
Kumar R;Bukowski MJ;Wider JM;Reynolds CA;Calo L;Lepore B;Tousignant R;Jones M;Przyklenk K;Sanderson TH
全局性脑缺血/再灌注可引起大脑脆弱区域的神经元损伤，导致线粒体功能障碍和随后的神经元死亡。神经元死亡的诱导是由线粒体释放细胞色素c （cyt c）介导的，尽管线粒体外膜通透性明显增加。然而，要释放cyt c，首先必须将cyt c从由Opa1寡聚物控制的嵴连接中解放出来。Opa1有两个已知的功能：维持嵴连接和线粒体融合。这些作用表明，在缺血/再灌注过程中，Opa1可能在控制cyt c释放和线粒体融合/裂变过程中发挥核心作用。为了研究这一概念，我们首先利用体外实时成像来观察线粒体的动态变化。氧-葡萄糖剥夺（OGD）培养的神经元诱导了两期线粒体断裂：(i)在OGD期间断裂，没有细胞凋亡激活，然后在再氧化后线粒体网络融合；（ii）随后广泛的断裂和细胞凋亡激活，在细胞死亡之前。接下来，我们在大鼠全脑缺血模型中评估了线粒体再灌注状态的变化。用共聚焦显微镜和电子显微镜对线粒体形态学的评估显示，全脑缺血后也有类似的碎片化诱导。线粒体断裂在时间上与特定的凋亡事件一致，包括cyt c释放、caspase 3/7激活，以及融合蛋白Opa1的释放。此外，我们发现了再灌注过程中Opa1复合物丢失的证据，电镜显微照片显示全脑缺血后嵴结构丢失。这些数据提供了新的证据，暗示在全脑缺血后，Opa1改变和线粒体动力学功能障碍之间存在时间联系。
Global brain ischemia/reperfusion induces neuronal damage in vulnerable brain regions, leading to mitochondrial dysfunction and subsequent neuronal death. Induction of neuronal death is mediated by release of cytochrome c (cyt c) from the mitochondria though a well-characterized increase in outer mitochondrial membrane permeability. However, for cyt c to be released it is first necessary for cyt c to be liberated from the cristae junctions which are gated by Opa1 oligomers. Opa1 has two known functions: maintenance of the cristae junction and mitochondrial fusion. These roles suggest that Opa1 could play a central role in both controlling cyt c release and mitochondrial fusion/fission processes during ischemia/reperfusion. To investigate this concept, we first utilized in vitro real-time imaging to visualize dynamic changes in mitochondria. Oxygen-glucose deprivation (OGD) of neurons grown in culture induced a dual-phase mitochondrial fragmentation profile: (i) fragmentation during OGD with no apoptosis activation, followed by fusion of mitochondrial networks after reoxygenation and a (ii) subsequent extensive fragmentation and apoptosis activation that preceded cell death. We next evaluated changes in mitochondrial dynamic state during reperfusion in a rat model of global brain ischemia. Evaluation of mitochondrial morphology with confocal and electron microscopy revealed a similar induction of fragmentation following global brain ischemia. Mitochondrial fragmentation aligned temporally with specific apoptotic events, including cyt c release, caspase 3/7 activation, and interestingly, release of the fusion protein Opa1. Moreover, we uncovered evidence of loss of Opa1 complexes during the progression of reperfusion, and electron microscopy micrographs revealed a loss of cristae architecture following global brain ischemia. These data provide novel evidence implicating a temporal connection between Opa1 alterations and dysfunctional mitochondrial dynamics following global brain ischemia.
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DOI：
10.1016/j.bbadis.2009.09.002
发表时间：
2010-01
影响因子：
6.2
作者：
Niizuma, Kuniyasu;Yoshioka, Hideyuki;Chen, Hai;Kim, Gab Seok;Jung, Joo Eun;Katsu, Masataka;Okami, Nobuya;Chan, Pak H.
通讯作者：
Chan, Pak H.
影响因子：
9.3
作者：
Sobrado M;Ramirez BG;Neria F;Lizasoain I;Arbones ML;Minami T;Redondo JM;Moro MA;Cano E
通讯作者：
Cano E
影响因子：
8.2
作者：
Makino, A.;Scott, B. T.;Dillmann, W. H.
通讯作者：
Dillmann, W. H.
影响因子：
12.4
作者：
Estaquier, J.;Arnoult, D.
通讯作者：
Arnoult, D.
影响因子：
4.8
作者：
Olichon, A;Baricault, L;Lenaers, G
通讯作者：
Lenaers, G