Permeability transition pore-mediated mitochondrial superoxide flashes mediate an early inhibitory effect of amyloid beta1-42 on neural progenitor cell proliferation.
Permeability transition pore-mediated mitochondrial superoxide flashes mediate an early inhibitory effect of amyloid beta1-42 on neural progenitor cell proliferation.
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DOI：
10.1016/j.neurobiolaging.2013.11.002
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发表时间：
2014-05
影响因子：
4.2
通讯作者：
Cheng A
中科院分区：
文献类型：
--
作者：
Hou Y;Ghosh P;Wan R;Ouyang X;Cheng H;Mattson MP;Cheng A
活性氧（ROS）引起的细胞损伤和神经发生改变与AD的病因学和淀粉样β肽（Aβ）的致病作用有关;其潜在机制和Aβ触发的早期氧化细胞内事件尚未确定。在本研究中，我们发现，小鼠胚胎皮质神经祖细胞表现出间歇性自发线粒体超氧化物（SO）闪光，需要线粒体渗透性转换孔（mPTPs）的瞬时开放。在暴露于聚集性淀粉样β-肽（Aβ1-42）的前6 - 24小时内，NPC中线粒体SO闪光活性的发生率增加，表明瞬时mPTP开放增加。随后，SO闪光频率逐渐降低，并在暴露于Aβ1-42的48 - 72小时之间停止，在此期间，整体细胞ROS增加，线粒体膜电位降低，细胞色素C从线粒体释放，细胞变性。抑制mPTPs和选择性减少线粒体SO闪光可显著减轻Aβ1-42对NPC增殖和存活的负面影响。我们的研究结果表明，在Aβ1-42对NPC的不良影响中，mPTP介导的线粒体SO产生的爆发是相对早期和关键的事件。如果Aβ通过类似的机制抑制AD患者脑中的NPC增殖，那么抑制mPTP介导的超氧化物闪光的干预措施有望保护NPC免受Aβ的不良影响。
Cellular damage by reactive oxygen species (ROS) and altered neurogenesis are implicated in the etiology of AD and the pathogenic actions of amyloid β-peptide (Aβ); the underlying mechanisms and the early oxidative intracellular events triggered by Aβ are not established. In the present study, we found that mouse embryonic cortical neural progenitor cells exhibit intermittent spontaneous mitochondrial superoxide (SO) flashes that require transient opening of mitochondrial permeability transition pores (mPTPs). The incidence of mitochondria SO flash activity in NPCs increased during the first 6 – 24 hours of exposure to aggregating amyloid β-peptide (Aβ1-42), indicating an increase in transient mPTP opening. Subsequently, the SO flash frequency progressively decreased and ceased between 48 and 72 hours of exposure to Aβ1-42, during which time global cellular ROS increased, mitochondrial membrane potential decreased, cytochrome C was released from mitochondria and the cells degenerated. Inhibition of mPTPs and selective reduction in mitochondrial SO flashes significantly ameliorated the negative effects of Aβ1-42 on NPC proliferation and survival. Our findings suggest that mPTP-mediated bursts of mitochondrial SO production is a relatively early and pivotal event in the adverse effects of Aβ1-42 on NPCs. If Aβ inhibits NPC proliferation in the brains of AD patients by a similar mechanism, then interventions that inhibit mPTP-mediated superoxide flashes would be expected to protect NPCs against the adverse effects of Aβ.
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影响因子：
4.8
作者：
Caspersen, C;Wang, N;Yan, SD
通讯作者：
Yan, SD
影响因子：
4.8
作者：
Cho, Sunghee;Szeto, Hazel H.;Pinto, John T.
通讯作者：
Pinto, John T.
DOI：
10.1042/bss0660167
发表时间：
1999-01-01
期刊：
MITOCHONDRIA AND CELL DEATH
影响因子：
--
作者：
Crompton, M;Virji, S;Ward, JM
通讯作者：
Ward, JM
影响因子：
4.2
作者：
Faure, A.;Verret, L.;Delatour, B.
通讯作者：
Delatour, B.
影响因子：
6.4
作者：
Cotman, CW;Su, JH
通讯作者：
Su, JH