Chitkara College of Pharmacy, Chitkara University, Punjab, India.
Chitkara College of Pharmacy, Chitkara University, Punjab, India.
Mitochondrion. 2021 May;58:213-226. doi: 10.1016/j.mito.2021.03.009. Epub 2021 Mar 26.
Epileptogenesis is most commonly associated with neurodegeneration and a bioenergetic defect attributing to the fact that mitochondrial dysfunction plays a key precursor for neuronal death. Mitochondria are the essential organelle of neuronal cells necessary for certain neurophysiological processes like neuronal action potential activity and synaptic transmission. The mitochondrial dysfunction disrupts calcium homeostasis leading to inhibitory interneuron dysfunction and increasing the excitatory postsynaptic potential. In epilepsy, the prolonged repetitive neuronal activity increases the excessive demand for energy and acidosis in the brain further increasing the intracellular calcium causing neuronal death. Similarly, the mitochondrial damage also leads to the decline of energy by dysfunction of the electron transport chain and abnormal production of the ROS triggering the apoptotic neuronal death. Thus, the elevated level of cytosolic calcium causes the mitochondria DNA damage coinciding with mtROS and releasing the cytochrome c binding to Apaf protein further initiating the apoptosis resulting in epileptic encephalopathies. The various genetic and mRNA studies of epilepsy have explored the various pathogenic mutations of genes affecting the mitochondria functioning further initiating the neuronal excitotoxicity. Based on the results of previous studies, the recent therapeutic approaches are targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria and hold great promise to attenuate epileptogenesis. Therefore, the current review emphasizes the emerging insights to uncover the relation between mitochondrial dysfunction and ROS generation contributing to mechanisms underlying epileptic seizures.
癫痫发生最常与神经退行性变和生物能量缺陷有关，这归因于线粒体功能障碍在神经元死亡的前体中起着关键作用。线粒体是神经元细胞的必需细胞器，对于神经元动作电位活动和突触传递等某些神经生理过程是必需的。线粒体功能障碍破坏钙稳态，导致抑制性中间神经元功能障碍，并增加兴奋性突触后电位。在癫痫中，长时间的重复神经元活动增加了大脑对能量和酸中毒的过度需求，进一步增加细胞内钙导致神经元死亡。同样，线粒体损伤也会导致电子传递链功能障碍和 ROS 的异常产生，从而引发凋亡性神经元死亡，从而导致能量下降。触发凋亡性神经元死亡。因此，细胞溶质钙水平的升高会导致线粒体 DNA 损伤，同时伴有 mtROS 的释放，并与 Apaf 蛋白结合的细胞色素 c 进一步引发凋亡，导致癫痫性脑病。癫痫的各种遗传和 mRNA 研究探索了影响线粒体功能的各种致病基因突变，进一步引发神经元兴奋性毒性。基于先前研究的结果，最近的治疗方法针对基本的线粒体过程，如能量代谢或自由基生成，或疾病相关蛋白与线粒体的特定相互作用，并具有减轻癫痫发生的巨大潜力。因此，目前的综述强调了揭示线粒体功能障碍与 ROS 生成之间关系的新见解，这些关系有助于阐明癫痫发作的机制。
