Increased mitochondrial fission and volume density by blocking glutamate excitotoxicity protect glaucomatous optic nerve head astrocytes.
Increased mitochondrial fission and volume density by blocking glutamate excitotoxicity protect glaucomatous optic nerve head astrocytes.
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DOI：
10.1002/glia.22781
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发表时间：
2015-05
期刊：
影响因子：
6.2
通讯作者：
Perkins, Guy A.
中科院分区：
文献类型：
--
作者：
Ju, Won-Kyu;Kim, Keun-Young;Noh, You Hyun;Hoshijima, Masahiko;Lukas, Thomas J.;Ellisman, Mark H.;Weinreb, Robert N.;Perkins, Guy A.
青光眼神经变性患者视神经头（ONH）的网层区出现星形胶质细胞结构和功能异常。谷氨酸兴奋性毒性介导的线粒体改变与实验性青光眼有关。然而，谷氨酸兴奋毒性、线粒体改变和ONH星形胶质细胞在青光眼发病机制中的关系尚不清楚。我们发现功能性n -甲基-d-天冬氨酸（NMDA）受体（NRs）存在于人类ONH星形胶质细胞中，青光眼人类ONH星形胶质细胞中NRs和谷氨酸-天冬氨酸转运体的表达水平升高。青光眼人ONH星形细胞表现出线粒体分裂，这与动力蛋白相关蛋白1的表达增加及其丝氨酸616的磷酸化有关。在BAC ALDH1L1 eGFP或Thy1-CFP转基因小鼠中，NMDA处理导致神经胶质层星形胶质细胞轴突丢失、形态肥大和线粒体分裂。在人ONH星形胶质细胞中，NMDA体外处理通过减少线粒体长度和数量触发线粒体分裂，从而降低线粒体体积密度。然而，美金刚阻断兴奋毒性（MEM）通过增加线粒体长度、数量和体积密度来阻止这些改变。在青光眼DBA/2J （D2）小鼠中，MEM阻断兴奋毒性可抑制胶质层星形胶质细胞的形态学改变以及线粒体数量和体积密度的增加。然而，阻断兴奋毒性降低了D2青光眼小鼠胶质层星形胶质细胞和轴突的自噬体/自溶体体积密度。这些发现证明，阻断兴奋毒性可通过增加线粒体分裂、增加线粒体体积密度和长度、减少自噬体/自溶体的形成来阻止青光眼神经退行性变中ONH星形胶质细胞功能障碍。
Abnormal structure and function of astrocytes have been observed within the lamina cribrosa region of the optic nerve head (ONH) in glaucomatous neurodegeneration. Glutamate excitotoxicity-mediated mitochondrial alteration has been implicated in experimental glaucoma. However, the relationships among glutamate excitotoxicity, mitochondrial alteration and ONH astrocytes in the pathogenesis of glaucoma remain unknown. We found that functional N-methyl-d-aspartate (NMDA) receptors (NRs) are present in human ONH astrocytes and that glaucomatous human ONH astrocytes have increased expression levels of NRs and the glutamate aspartate transporter. Glaucomatous human ONH astrocytes exhibit mitochondrial fission that is linked to increased expression of dynamin-related protein 1 and its phosphorylation at Serine 616. In BAC ALDH1L1 eGFP or Thy1-CFP transgenic mice, NMDA treatment induced axon loss as well as hypertrophic morphology and mitochondrial fission in astrocytes of the glial lamina. In human ONH astrocytes, NMDA treatment in vitro triggered mitochondrial fission by decreasing mitochondrial length and number, thereby reducing mitochondrial volume density. However, blocking excitotoxicity by memantine (MEM) prevented these alterations by increasing mitochondrial length, number and volume density. In glaucomatous DBA/2J (D2) mice, blocking excitotoxicity by MEM inhibited the morphological alteration as well as increased mitochondrial number and volume density in astrocytes of the glial lamina. However, blocking excitotoxicity decreased autophagosome/autolysosome volume density in both astrocytes and axons in the glial lamina of glaucomatous D2 mice. These findings provide evidence that blocking excitotoxicity prevents ONH astrocyte dysfunction in glaucomatous neurodegeneration by increasing mitochondrial fission, increasing mitochondrial volume density and length, and decreasing autophagosome/autolysosome formation.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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4.4
作者：
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