Induction of cytochrome c-mediated apoptosis by amyloid β 25-35 requires functional mitochondria
Induction of cytochrome c-mediated apoptosis by amyloid β 25-35 requires functional mitochondria
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DOI：
10.1016/s0006-8993(02)02256-4
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发表时间：
2002-03-29
期刊：
影响因子：
2.9
通讯作者：
Oliveira, CR
中科院分区：
文献类型：
--
作者：
Cardoso, SM;Swerdlow, RH;Oliveira, CR
越来越多的数据表明线粒体和氧化应激在神经退行性细胞凋亡中发挥着核心作用。我们之前证明，淀粉样蛋白-β 肽 25-35 (Abeta 25-35) 对培养细胞的毒性是通过其对功能线粒体的影响介导的。在这项研究中，我们进一步探讨了 AD 25-35 可能通过改变线粒体生理学来诱导细胞凋亡的假设。暴露于星孢菌素 (STS) 或 Abeta 25-35 的 Ntera2 (NT2 rho+) 人畸胎癌细胞中的线粒体被发现释放细胞色素 c。随后激活 caspase 9 和 3。然而，尽管缺乏功能性电子传递链 (ETC)，但线粒体 DNA 耗尽的 NT2 细胞（rho0 细胞）仍保持正常线粒体膜电位 (Deltapsi(m))，仅通过 STS 即可证明细胞色素 c 释放和 caspase 激活。我们进一步观察到，在用 STS 处理的 rho(+) 和 rho(0) 细胞中，活性氧 (ROS) 产生增加，还原型谷胱甘肽 (GSH) 水平降低，但仅在用 Abeta 25-35 处理的 rho(+) 细胞中。我们得出的结论是，在体外条件下，只有当功能性线粒体 ETC 存在时，Abeta 才能诱导氧化应激和细胞凋亡。 (C) 2002 Elsevier Science B.V. 保留所有权利。
Accumulating data suggest a central role for mitochondria and oxidative stress in neurodegenerative apoptosis. We previously demonstrated that amyloid-beta peptide 25-35 (Abeta 25-35) toxicity in cultured cells is mediated by its effects on functioning mitochondria. In this study, we further explored the hypothesis that AD 25-35 might induce apoptotic cell death by altering mitochondrial physiology. Mitochondria in Ntera2 (NT2 rho+) human teratocarcinoma cells exposed to either staurosporine (STS) or Abeta 25-35 were found to release cytochrome c. with subsequent activation of caspases 9 and 3. However, NT2 cells depleted of mitochondrial DNA (rho0 cells), which maintain a normal mitochondrial membrane potential (Deltapsi(m)) despite the absence of a functional electron transport chain (ETC), demonstrated cytochrome c release and caspase activation only with STS. We further observed increased reactive oxygen species (ROS) production and decreased reduced glutathione (GSH) levels in rho(+) and rho(0) cells treated with STS, but only in rho(+) cells treated with Abeta 25-35. We conclude that under in vitro conditions, Abeta can induce oxidative stress and apoptosis only when a functional mitochondrial ETC is present. (C) 2002 Elsevier Science B.V. All rights reserved.