Pivovarova Natalia B, Stanika Ruslan I, Watts Charlotte A, Brantner Christine A, Smith Carolyn L, Andrews S Brian
Laboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
J Neurochem. 2008 Mar;104(6):1686-99. doi: 10.1111/j.1471-4159.2007.05080.x. Epub 2007 Nov 23.
In 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.
在中枢神经元中，NMDA受体的过度刺激会导致线粒体钙过度积累和损伤，这是兴奋毒性死亡的关键步骤。这就增加了一种可能性，即对钙超载诱导的线粒体损伤低敏感性可能是抗兴奋毒性神经元的特征。在本研究中，我们利用了两种预处理诱导的兴奋毒性抗性互补模型，以证明耐NMDA的海马神经元中钙依赖性线粒体损伤减少。我们进一步确定了线粒体钙处理的适应性变化，这些变化有助于增强线粒体的完整性。在这两种模型中，耐受性增强都与线粒体膜电位和结构的更好保存有关。在第一种表现出适度神经保护作用的模型中，线粒体依赖性钙失调被延迟，尽管胞质和线粒体钙负荷在数量上没有变化，这表明线粒体钙容量增强导致损伤减少。相比之下，第二种表现出强烈神经保护作用的模型，由于NMDA受体表面表达下调降低了钙负荷，显示出进一步延迟的钙失调和减少的线粒体损伤。减少钙内流也改变了在钙负荷线粒体中形成的钙缓冲沉淀物的化学成分。因此，线粒体钙负荷降低似乎是高耐受性细胞中强大神经保护作用的主要因素。
