Oxidative stress-induced apoptosis in neurons correlates with mitochondrial DNA base excision repair pathway imbalance.
Oxidative stress-induced apoptosis in neurons correlates with mitochondrial DNA base excision repair pathway imbalance.
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DOI：
10.1093/nar/gki759
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发表时间：
2005
影响因子：
14.9
通讯作者：
LeDoux SP
中科院分区：
文献类型：
--
作者：
Harrison JF;Hollensworth SB;Spitz DR;Copeland WC;Wilson GL;LeDoux SP
内源性氧化应激可导致神经变性。原代小脑颗粒细胞在这项研究中，以确定线粒体DNA（mtDNA）修复缺陷与氧化应激诱导的神经元细胞凋亡。与原代星形胶质细胞相比，颗粒细胞表现出显著更高的细胞内氧化状态，以及还原剂（如谷胱甘肽）和氧化还原敏感性信号分子（如AP核酸内切酶/氧化还原效应因子-1）的增加。小脑颗粒培养物也表现出对外源性氧化应激的敏感性增加。甲萘醌（50 μ M）在颗粒细胞mtDNA中产生的损伤是星形胶质细胞的两倍，颗粒细胞mtDNA修复的效率明显降低。在这些神经元培养物中，修复氧化性mtDNA损伤的能力降低与线粒体启动的细胞凋亡密切相关。有趣的是，线粒体活动的启动子碱基切除修复（BER），双功能糖基化酶/AP裂解酶以及AP核酸内切酶，显着较高的小脑颗粒细胞相比，星形胶质细胞。线粒体AP核酸内切酶活性的增加与聚合酶γ活性的降低相结合，可能导致氧化BER的失衡，从而导致用甲萘醌处理时神经元中mtDNA损伤的产生和持续增加。这项研究提供了证据，神经元mtDNA修复能力与氧化应激相关的神经变性。
Neurodegeneration can occur as a result of endogenous oxidative stress. Primary cerebellar granule cells were used in this study to determine if mitochondrial DNA (mtDNA) repair deficiencies correlate with oxidative stress-induced apoptosis in neuronal cells. Granule cells exhibited a significantly higher intracellular oxidative state compared with primary astrocytes as well as increases in reductants, such as glutathione, and redox sensitive signaling molecules, such as AP endonuclease/redox effector factor-1. Cerebellar granule cultures also exhibited an increased susceptibility to exogenous oxidative stress. Menadione (50 μM) produced twice as many lesions in granule cell mtDNA compared with astrocytes, and granule cell mtDNA repair was significantly less efficient. A decreased capacity to repair oxidative mtDNA damage correlates strongly with mitochondrial initiated apoptosis in these neuronal cultures. Interestingly, the mitochondrial activities of initiators for base excision repair (BER), the bifunctional glycosylase/AP lyases as well as AP endonuclease, were significantly higher in cerebellar granule cells compared with astrocytes. The increased mitochondrial AP endonuclease activity in combination with decreased polymerase γ activity may cause an imbalance in oxidative BER leading to an increased production and persistence of mtDNA damage in neurons when treated with menadione. This study provides evidence linking neuronal mtDNA repair capacity with oxidative stress-related neurodegeneration.
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影响因子：
19
作者：
Green, D;Kroemer, G
通讯作者：
Kroemer, G
影响因子：
3.3
作者：
Hudson, EK;Hogue, BA;Hansford, RG
通讯作者：
Hansford, RG
影响因子：
3.8
作者：
Araneda, S;Mermet, N;Radicella, JP
通讯作者：
Radicella, JP
DOI：
10.1016/0006-291x(90)90497-b
发表时间：
1990-08-16
影响因子：
3.1
作者：
IKEBE, S;TANAKA, M;OZAWA, T
通讯作者：
OZAWA, T
影响因子：
4.8
作者：
Kudin, AP;Bimpong-Buta, NYB;Kunz, WS
通讯作者：
Kunz, WS