A new vicious cycle involving glutamate excitotoxicity, oxidative stress and mitochondrial dynamics.
A new vicious cycle involving glutamate excitotoxicity, oxidative stress and mitochondrial dynamics.
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涉及谷氨酸兴奋性，氧化应激和线粒体动力学的新的恶性循环。
DOI：
10.1038/cddis.2011.117
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发表时间：
2011-12-08
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
谷氨酸兴奋性毒性导致神经退行性疾病中的线粒体碎片化，由一氧化氮和动力蛋白相关蛋白1（线粒体外膜分裂蛋白）的S-亚硝基化介导。视神经萎缩基因1（Optic atrophy gene 1，OPA 1）是一种重要的线粒体融合内膜蛋白。常染色体显性视神经萎缩（ADOA）是由OPA 1基因突变引起的一种神经退行性疾病，主要累及视网膜神经节细胞（RGC）。在这里，我们发现，在ADOA模型中OPA 1缺乏影响N-甲基-D-天冬氨酸（NMDA）受体的表达，这是参与谷氨酸兴奋毒性和氧化应激。Opa 1 enu/+小鼠显示RGCs的缓慢进行性损失、星形胶质细胞和小胶质细胞的活化以及通过电子断层扫描发现的视神经头中的明显线粒体分裂。通过Western blot和免疫组织化学测定，Opa 1 enu/+小鼠视网膜中NMDA受体（NR 1、2A和2B）的表达显著增加。超氧化物歧化酶2（SOD 2）表达显著降低，凋亡途径被激活，Bax表达增加，磷酸化Bad和BcL-xL表达减少。我们的研究结果最终表明，不仅谷氨酸兴奋性毒性和/或氧化应激改变线粒体分裂/融合，但线粒体分裂/融合的不平衡反过来导致NMDA受体上调和氧化应激。因此，我们提出了一个新的恶性循环参与神经变性，包括谷氨酸兴奋毒性，氧化应激和线粒体动力学。
Glutamate excitotoxicity leads to fragmented mitochondria in neurodegenerative diseases, mediated by nitric oxide and S-nitrosylation of dynamin-related protein 1, a mitochondrial outer membrane fission protein. Optic atrophy gene 1 (OPA1) is an inner membrane protein important for mitochondrial fusion. Autosomal dominant optic atrophy (ADOA), caused by mutations in OPA1, is a neurodegenerative disease affecting mainly retinal ganglion cells (RGCs). Here, we showed that OPA1 deficiency in an ADOA model influences N-methyl-D-aspartate (NMDA) receptor expression, which is involved in glutamate excitotoxicity and oxidative stress. Opa1enu/+ mice show a slow progressive loss of RGCs, activation of astroglia and microglia, and pronounced mitochondrial fission in optic nerve heads as found by electron tomography. Expression of NMDA receptors (NR1, 2A, and 2B) in the retina of Opa1enu/+ mice was significantly increased as determined by western blot and immunohistochemistry. Superoxide dismutase 2 (SOD2) expression was significantly decreased, the apoptotic pathway was activated as Bax was increased, and phosphorylated Bad and BcL-xL were decreased. Our results conclusively demonstrate that not only glutamate excitotoxicity and/or oxidative stress alters mitochondrial fission/fusion, but that an imbalance in mitochondrial fission/fusion in turn leads to NMDA receptor upregulation and oxidative stress. Therefore, we propose a new vicious cycle involved in neurodegeneration that includes glutamate excitotoxicity, oxidative stress, and mitochondrial dynamics.
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影响因子：
4.8
作者：
Jahani-Asl, Arezu;Pilon-Larose, Karine;Slack, Ruth S.
通讯作者：
Slack, Ruth S.
影响因子：
4.2
作者：
JOHNSTON, PB;GASTER, RN;TRIPATHI, RC
通讯作者：
TRIPATHI, RC
影响因子：
4.4
作者：
Heiduschka, Peter;Schnichels, Sven;Alavi, Marcel V.
通讯作者：
Alavi, Marcel V.
影响因子：
4
作者：
Fuhrmann, N.;Alavi, M. V.;Wissinger, B.
通讯作者：
Wissinger, B.
影响因子：
5.3
作者：
Alavi, Marcel V.;Fuhrmann, Nico;Wissinger, Bernd
通讯作者：
Wissinger, Bernd