Department of Anatomy & Neurobiology, University of California, Irvine, USA.
Department of Anatomy & Neurobiology, University of California, Irvine, USA; Department of Neurology, University of California, Irvine, USA.
Exp Neurol. 2018 Apr;302:181-195. doi: 10.1016/j.expneurol.2018.01.012. Epub 2018 Jan 24.
Excitotoxic Zn and Ca accumulation contributes to neuronal injury after ischemia or prolonged seizures. Synaptically released Zn can enter postsynaptic neurons via routes including voltage sensitive Ca channels (VSCC), and, more rapidly, through Ca permeable AMPA channels. There are also intracellular Zn binding proteins which can either buffer neuronal Zn influx or release bound Zn into the cytosol during pathologic conditions. Studies in culture highlight mitochondria as possible targets of Zn; cytosolic Zn can enter mitochondria and induce effects including loss of mitochondrial membrane potential (ΔΨ), mitochondrial swelling, and reactive oxygen species (ROS) generation. While brief (5 min) neuronal depolarization (to activate VSCC) in the presence of 300 μM Zn causes substantial delayed neurodegeneration, it only mildly impacts acute mitochondrial function, raising questions as to contributions of Zn-induced mitochondrial dysfunction to neuronal injury. Using brief high (90 mM) K/Zn exposures to mimic neuronal depolarization and extracellular Zn accumulation as may accompany ischemia in vivo, we examined effects of disrupted cytosolic Zn buffering and/or the presence of Ca, and made several observations: 1. Mild disruption of cytosolic Zn buffering-while having little effects alone-markedly enhanced mitochondrial Zn accumulation and dysfunction (including loss of ∆Ψ, ROS generation, swelling and respiratory inhibition) caused by relatively low (10-50 μM) Zn with high K. 2. The presence of Ca during the Zn exposure decreased cytosolic and mitochondrial Zn accumulation, but markedly exacerbated the consequent dysfunction. 3. Paralleling effects on mitochondria, disruption of buffering and presence of Ca enhanced Zn-induced neurodegeneration. 4. Zn chelation after the high K/Zn exposure attenuated both ROS production and neurodegeneration, supporting the potential utility of delayed interventions. Taken together, these data lend credence to the idea that in pathologic states that impair cytosolic Zn buffering, slow uptake of Zn along with Ca into neurons via VSCC can disrupt the mitochondria and induce neurodegeneration.
兴奋性 Zn 和 Ca 积累导致缺血或长时间癫痫发作后的神经元损伤。突触释放的 Zn 可以通过包括电压敏感 Ca 通道 (VSCC) 的途径进入突触后神经元，并且更迅速地通过 Ca 通透性 AMPA 通道进入。还有细胞内 Zn 结合蛋白，它们可以在病理条件下缓冲神经元 Zn 内流或将结合的 Zn 释放到细胞质中。在培养物中的研究强调了线粒体作为 Zn 的可能靶标；细胞质中的 Zn 可以进入线粒体并诱导包括线粒体膜电位 (ΔΨ) 丧失、线粒体肿胀和活性氧 (ROS) 生成在内的效应。虽然短暂的 (5 分钟) 神经元去极化 (激活 VSCC) 在存在 300μM Zn 的情况下会导致大量的延迟神经退行性变，但它仅对急性线粒体功能产生轻微影响，这引发了关于 Zn 诱导的线粒体功能障碍对神经元损伤的贡献的问题。使用短暂的高 (90mM) K/Zn 暴露来模拟神经元去极化和细胞外 Zn 积累，如体内缺血可能伴随的那样，我们检查了破坏细胞质 Zn 缓冲和/或 Ca 存在的影响，并得出了以下几点观察结果：1. 细胞质 Zn 缓冲的轻度破坏——尽管单独作用不大——显著增强了由相对较低 (10-50μM) Zn 和高 K 引起的线粒体 Zn 积累和功能障碍 (包括 ΔΨ 丧失、ROS 生成、肿胀和呼吸抑制)。2. Zn 暴露期间 Ca 的存在降低了细胞质和线粒体 Zn 积累，但显著加剧了随后的功能障碍。3. 与线粒体平行的效应，缓冲破坏和 Ca 的存在增强了 Zn 诱导的神经退行性变。4. Zn 螯合在高 K/Zn 暴露后减轻了 ROS 生成和神经退行性变，支持延迟干预的潜在效用。总之，这些数据为这样一种观点提供了可信度，即在损害细胞质 Zn 缓冲的病理状态下，通过 VSCC 缓慢摄取 Zn 和 Ca 进入神经元可以破坏线粒体并诱导神经退行性变。
