Neuronal hypoxia disrupts mitochondrial fusion.
Neuronal hypoxia disrupts mitochondrial fusion.
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DOI：
10.1016/j.neuroscience.2015.05.078
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发表时间：
2015-08-20
期刊：
影响因子：
3.3
通讯作者：
Kumar R
中科院分区：
文献类型：
--
作者：
Sanderson TH;Raghunayakula S;Kumar R
脑缺血再灌注损伤可导致易损神经元的死亡和广泛的脑损伤。众所周知，细胞色素c （cyto c）的线粒体释放是神经元死亡的标志，然而，这种释放背后的分子事件在很大程度上是未知的。我们验证了细胞c的释放是由位于线粒体内膜的嵴结构维持蛋白optic atrophy 1 （OPA1）的破坏所调节的假设。我们模拟离体大鼠原代神经元缺血再灌注，研究线粒体中OPA1的释放、OPA1寡聚物的分解以及伴随的线粒体动态功能障碍。我们发现缺血/再灌注诱导细胞c释放和细胞死亡，这与OPA1的多种变化相对应，包括：(i)线粒体融合蛋白OPA1从线粒体到细胞质的易位，（ii） OPA1短异构体的增加，提示蛋白质水解过程，（iii）线粒体中OPA1寡聚物的分解，以及（iv）线粒体裂变增加。因此，我们提出了新的证据，证明线粒体中细胞c的释放与线粒体融合的破坏之间存在联系。
Brain ischemia/reperfusion injury results in death of vulnerable neurons and extensive brain damage. It is well known that mitochondrial release of cytochrome c (cyto c) is a hallmark of neuronal death, however the molecular events underlying this release are largely unknown. We tested the hypothesis that cyto c release is regulated by breakdown of the cristae architecture maintenance protein, optic atrophy 1 (OPA1), located in the inner mitochondrial membrane. We simulated ischemia/reperfusion in isolated primary rat neurons and interrogated OPA1 release from the mitochondria, OPA1 oligomeric breakdown, and concomitant dysfunction of mitochondrial dynamic state. We found that ischemia/reperfusion induces cyto c release and cell death that corresponds to multiple changes in OPA1, including: (i) translocation of the mitochondrial fusion protein OPA1 from the mitochondria to the cytosol, (ii) increase in the short isoform of OPA1, suggestive of proteolytic processing, (iii) breakdown of OPA1 oligomers in the mitochondria, and (iv) increased mitochondrial fission. Thus, we present novel evidence of a connection between release of cyto c from mitochondria and disruption of the mitochondrial fusion.