Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons
Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons
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DOI：
10.1038/sj.emboj.7601253
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发表时间：
2006-08-23
期刊：
影响因子：
11.4
通讯作者：
Bossy-Wetzel, Ella
中科院分区：
文献类型：
--
作者：
Barsoum, Mark J.;Yuan, Hua;Bossy-Wetzel, Ella
线粒体在神经元突起中以管状细胞器的形式存在。在这里，我们报道了线粒体在原代培养皮层神经元中对一氧化氮（NO）的反应中发生深刻的裂变。一氧化氮引起的线粒体分裂早在神经突损伤和神经元细胞死亡之前就发生了。此外，裂变还伴随着线粒体的超微结构损伤、自噬、ATP下降和自由基的产生。裂变有时是不对称的，可以是可逆的。引人注目的是，线粒体分裂也是体内缺血性中风的早期事件。Mitofusin 1（Mfn1）或显性阴性的Dynamin相关蛋白1（Drp1(K38A)）抑制NO、鱼tenone和Amyloid-beta肽诱导的线粒体分裂。相反，过表达Drp1或Fis1会引起分裂并增加神经元的损失。重要的是，Mfn1和Drp1（K38A）减轻了no诱导的神经元细胞死亡。因此，持续的线粒体分裂可能在no介导的神经毒性中起因果作用。
Mitochondria are present as tubular organelles in neuronal projections. Here, we report that mitochondria undergo profound fission in response to nitric oxide (NO) in cortical neurons of primary cultures. Mitochondrial fission by NO occurs long before neurite injury and neuronal cell death. Furthermore, fission is accompanied by ultrastructural damage of mitochondria, autophagy, ATP decline and generation of free radicals. Fission is occasionally asymmetric and can be reversible. Strikingly, mitochondrial fission is also an early event in ischemic stroke in vivo. Mitofusin 1 (Mfn1) or dominant-negative Dynamin related protein 1 (Drp1(K38A)) inhibits mitochondrial fission induced by NO, rotenone and Amyloid-beta peptide. Conversely, overexpression of Drp1 or Fis1 elicits fission and increases neuronal loss. Importantly, NO-induced neuronal cell death was mitigated by Mfn1 and Drp1(K38A). Thus, persistent mitochondrial fission may play a causal role in NO-mediated neurotoxicity.