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Mitochondrial dysfunction and role in spreading depolarization and seizure.
Journal of Computational Neuroscience ( IF 1.5 ) Pub Date : 2019-09-11 , DOI: 10.1007/s10827-019-00724-6
Patrick Toglia 1 , Ghanim Ullah 1
Affiliation  

The effect of pathological phenomena such as epileptic seizures and spreading depolarization (SD) on mitochondria and the potential feedback of mitochondrial dysfunction into the dynamics of those phenomena are complex and difficult to study experimentally due to the simultaneous changes in many variables governing neuronal behavior. By combining a model that accounts for a wide range of neuronal behaviors including seizures, normoxic SD, and hypoxic SD (HSD), together with a detailed model of mitochondrial function and intracellular Ca2+ dynamics, we investigate mitochondrial dysfunction and its potential role in recovery of the neuron from seizures, HSD, and SD. Our results demonstrate that HSD leads to the collapse of mitochondrial membrane potential and cellular ATP levels that recover only when normal oxygen supply is restored. Mitochondrial organic phosphate and pH gradients determine the strength of the depolarization block during HSD and SD, how quickly the cell enters the depolarization block when the oxygen supply is disrupted or potassium in the bath solution is raised beyond the physiological value, and how fast the cell recovers from SD and HSD when normal potassium concentration and oxygen supply are restored. Although not as dramatic as phosphate and pH gradients, mitochondrial Ca2+ uptake has a similar effect on neuronal behavior during these conditions.

中文翻译:

线粒体功能障碍及其在扩散去极化和癫痫发作中的作用。

诸如癫痫发作和扩散去极化 (SD) 等病理现象对线粒体的影响以及线粒体功能障碍对这些现象动力学的潜在反馈是复杂的,并且由于控制神经元行为的许多变量同时发生变化而难以通过实验研究。通过结合一个模型,该模型解释了包括癫痫发作、常氧 SD 和缺氧 SD (HSD) 在内的各种神经元行为,以及线粒体功能和细胞内 Ca 2+的详细模型在动力学方面,我们研究了线粒体功能障碍及其在神经元从癫痫发作、HSD 和 SD 中恢复中的潜在作用。我们的研究结果表明,HSD 导致线粒体膜电位和细胞 ATP 水平的崩溃,只有当正常的氧气供应恢复时才会恢复。线粒体有机磷酸盐和 pH 梯度决定了 HSD 和 SD 期间去极化块的强度,当氧气供应中断或浴液中的钾升高超过生理值时,细胞进入去极化块的速度,以及细胞进入去极化块的速度有多快当钾浓度和氧气供应恢复正常时,从 SD 和 HSD 中恢复。虽然不像磷酸盐和 pH 梯度那样剧烈,但线粒体 Ca 2+在这些情况下,摄取对神经元行为有类似的影响。
更新日期:2019-09-11
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