Reduced calcium-dependent mitochondrial damage underlies the reduced vulnerability of excitotoxicity-tolerant hippocampal neurons.
Reduced calcium-dependent mitochondrial damage underlies the reduced vulnerability of excitotoxicity-tolerant hippocampal neurons.
复制标题
钙依赖性线粒体损伤的减少是耐兴奋性毒性海马神经元脆弱性降低的基础。
DOI：
10.1111/j.1471-4159.2007.05080.x
复制
发表时间：
2008
影响因子：
4.7
通讯作者：
Andrews,SBrian
中科院分区：
文献类型：
--
作者：
Pivovarova,NataliaB;Stanika,RuslanI;Watts,CharlotteA;Brantner,ChristineA;Smith,CarolynL;Andrews,SBrian
J. Neurochem.(2008)104,1686–1699.摘要在中枢神经元中，NMDA受体的过度刺激导致线粒体钙积累和损伤过多，这是兴奋性毒性死亡的关键步骤。这提出了一种可能性，即对钙超载引起的线粒体损伤的敏感性较低可能是兴奋性毒性抵抗神经元的特征。在这项研究中，我们利用了两种互补的预处理诱导的兴奋毒性抵抗模型来证明 NMDA 耐受的海马神经元中钙依赖性线粒体损伤的减少。我们进一步确定了线粒体钙处理的适应性，从而增强了线粒体的完整性。在这两种模型中，耐受性的增强与线粒体膜电位和结构的保存改善有关。在第一个模型中，表现出适度的神经保护作用，尽管细胞质和线粒体钙负荷在数量上没有变化，但线粒体依赖性钙失调被延迟，这表明线粒体钙容量的增强可以减少损伤。相比之下，第二种模型表现出强大的神经保护作用，由于 NMDA 受体表面表达的下调抑制了钙负荷，因此进一步延迟了钙失调并减少了线粒体损伤。减少钙进入还改变了在钙负载线粒体中形成的钙缓冲沉淀物的化学成分。因此，线粒体钙负荷的减少似乎是高度耐受细胞中强大的神经保护作用的主要因素。
J. Neurochem.(2008)104,1686–1699.AbstractIn central neurons, over‐stimulation of NMDA receptors leads to excessive mitochondrial calcium accumulation and damage, which is a critical step in excitotoxic death. This raises the possibility that low susceptibility to calcium overload‐induced mitochondrial damage might characterize excitotoxicity‐resistant neurons. In this study, we have exploited two complementary models of preconditioning‐induced excitotoxicity resistance to demonstrate reduced calcium‐dependent mitochondrial damage in NMDA‐tolerant hippocampal neurons. We have further identified adaptations in mitochondrial calcium handling that account for enhanced mitochondrial integrity. In both models, enhanced tolerance was associated with improved preservation of mitochondrial membrane potential and structure. In the first model, which exhibited modest neuroprotection, mitochondria‐dependent calcium deregulation was delayed, even though cytosolic and mitochondrial calcium loads were quantitatively unchanged, indicating that enhanced mitochondrial calcium capacity accounts for reduced injury. In contrast, the second model, which exhibited strong neuroprotection, displayed further delayed calcium deregulation and reduced mitochondrial damage because downregulation of NMDA receptor surface expression depressed calcium loading. Reducing calcium entry also modified the chemical composition of the calcium‐buffering precipitates that form in calcium‐loaded mitochondria. It thus appears that reduced mitochondrial calcium loading is a major factor underlying the robust neuroprotection seen in highly tolerant cells.