Zn2+-induced disruption of neuronal mitochondrial function: Synergism with Ca2+, critical dependence upon cytosolic Zn2+ buffering, and contributions to neuronal injury.
Zn2+-induced disruption of neuronal mitochondrial function: Synergism with Ca2+, critical dependence upon cytosolic Zn2+ buffering, and contributions to neuronal injury.
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Zn2 诱导的神经元线粒体功能破坏：与 Ca2+ 的协同作用、对细胞质 Zn2 缓冲的严重依赖以及对神经元损伤的贡献。
DOI：
10.1016/j.expneurol.2018.01.012
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发表时间：
2018
影响因子：
5.3
通讯作者：
Weiss,JohnH
中科院分区：
文献类型：
--
作者：
Ji,SungG;Weiss,JohnH
兴奋性毒性Zn2+和Ca2+积累有助于缺血或长时间癫痫发作后的神经元损伤。突触释放的Zn2+可以通过电压敏感的Ca2+通道（VSCC）进入突触后神经元，更快速的是通过Ca2+可渗透的AMPA通道。细胞内还有一些Zn2+结合蛋白，它们可以缓冲神经元内流的Zn2+或在病理状态下将结合的Zn2+释放到细胞质中。培养研究表明，线粒体是Zn2+的可能靶点；胞浆中Zn2+可以进入线粒体并引起线粒体膜电位丧失（ΔΨm）、线粒体肿胀和活性氧（ROS）产生等影响。虽然在300 μM Zn2+存在下短暂（5 min）的神经元去极化（激活VSCC）会导致大量的延迟性神经退行性变，但它只会轻微影响急性线粒体功能，这就提出了Zn2+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（90 mM） K+/Zn2+暴露来模拟神经元去极化和细胞外Zn2+积累，这可能伴随着体内缺血，我们检查了破坏细胞质Zn2+缓冲和/或Ca2+存在的影响，并进行了以下观察：轻微破坏细胞质Zn2+缓冲，虽然单独作用不大，但明显增强了相对低（10-50 μM） Zn2+和高K+ 2引起的线粒体Zn2+积累和功能障碍（包括∆Ψm损失、ROS生成、肿胀和呼吸抑制）。在Zn2+暴露期间，Ca2+的存在降低了细胞内和线粒体Zn2+的积累，但明显加剧了随之而来的功能障碍。线粒体的平行效应，缓冲的破坏和Ca2+的存在增强了Zn2+诱导的神经变性。高K+/Zn2+暴露后的Zn2+螯合可以减弱ROS的产生和神经退行性变，支持延迟干预的潜在效用。综上所述，这些数据为以下观点提供了证据：在损害细胞质Zn2+缓冲的病理状态下，通过VSCC缓慢摄取Zn2+和Ca2+进入神经元可以破坏线粒体并诱导神经退行性变。
Excitotoxic Zn2+and Ca2+accumulation contributes to neuronal injury after ischemia or prolonged seizures. Synaptically released Zn2+can enter postsynaptic neurons via routes including voltage sensitive Ca2+channels (VSCC), and, more rapidly, through Ca2+permeable AMPA channels. There are also intracellular Zn2+binding proteins which can either buffer neuronal Zn2+influx or release bound Zn2+into the cytosol during pathologic conditions. Studies in culture highlight mitochondria as possible targets of Zn2+; cytosolic Zn2+can enter mitochondria and induce effects including loss of mitochondrial membrane potential (ΔΨm), mitochondrial swelling, and reactive oxygen species (ROS) generation. While brief (5 min) neuronal depolarization (to activate VSCC) in the presence of 300 μM Zn2+causes substantial delayed neurodegeneration, it only mildly impacts acute mitochondrial function, raising questions as to contributions of Zn2+-induced mitochondrial dysfunction to neuronal injury.Using brief high (90 mM) K+/Zn2+exposures to mimic neuronal depolarization and extracellular Zn2+accumulation as may accompany ischemiain vivo, we examined effects of disrupted cytosolic Zn2+buffering and/or the presence of Ca2+, and made several observations:1.Mild disruption of cytosolic Zn2+buffering—while having little effects alone—markedly enhanced mitochondrial Zn2+accumulation and dysfunction (including loss of ∆Ψm, ROS generation, swelling and respiratory inhibition) caused by relatively low (10–50 μM) Zn2+with high K+.2.The presence of Ca2+during the Zn2+exposure decreased cytosolic and mitochondrial Zn2+accumulation, but markedly exacerbated the consequent dysfunction.3.Paralleling effects on mitochondria, disruption of buffering and presence of Ca2+enhanced Zn2+-induced neurodegeneration.4.Zn2+chelation after the high K+/Zn2+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 Zn2+buffering, slow uptake of Zn2+along with Ca2+into neurons via VSCC can disrupt the mitochondria and induce neurodegeneration.