Yang Hanyu, Wang Lu, Zang Caixia, Yang Xu, Bao Xiuqi, Shang Junmei, Zhang Zihong, Liu Hui, Ju Cheng, Li Fangyuan, Yuan Fangyu, Zhang Dan
State Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Front Pharmacol. 2021 Mar 19;12:588003. doi: 10.3389/fphar.2021.588003. eCollection 2021.
Mitochondrial dysfunction is involved in the pathogenesis of Parkinson's disease (PD). Mitochondrial morphology is dynamic and precisely regulated by mitochondrial fission and fusion machinery. Aberrant mitochondrial fragmentation, which can result in cell death, is controlled by the mitochondrial fission protein, dynamin-related protein 1 (Drp1). Our previous results demonstrated that FLZ could correct mitochondrial dysfunction, but the effect of FLZ on mitochondrial dynamics remain uncharacterized. In this study, we investigated the effect of FLZ and the role of Drp1 on 1-methyl-4-phenylpyridinium (MPP)-induced mitochondrial fission in neurons. We observed that FLZ blocked Drp1, inhibited Drp1 enzyme activity, and reduced excessive mitochondrial fission in cultured neurons. Furthermore, by inhibiting mitochondrial fission and ROS production, FLZ improved mitochondrial integrity and membrane potential, resulting in neuroprotection. FLZ curtailed the reduction of synaptic branches of primary cultured dopaminergic neurons caused by MPP exposure, reduced abnormal fission, restored normal mitochondrial distribution in neurons, and exhibited protective effects on dopaminergic neurons. The research results were validated using an MPTP-induced PD mouse model. The results revealed that FLZ significantly reduced the mitochondrial translocation of Drp1 in the midbrain of PD mice, which, in turn, reduced the mitochondrial fragmentation in mouse substantia nigra neurons. FLZ also protected dopaminergic neurons in PD mice and increased the dopamine content in the striatum, which improved the motor coordination ability of the mice. These findings elucidate this newly discovered mechanism through which FLZ produces neuroprotection in PD.
线粒体功能障碍参与帕金森病（PD）的发病机制。线粒体形态是动态的，受线粒体分裂和融合机制精确调控。异常的线粒体碎片化可导致细胞死亡，其由线粒体分裂蛋白动力相关蛋白1（Drp1）控制。我们之前的结果表明FLZ可纠正线粒体功能障碍，但FLZ对线粒体动力学的影响仍未明确。在本研究中，我们研究了FLZ的作用以及Drp1在1-甲基-4-苯基吡啶鎓（MPP）诱导的神经元线粒体分裂中的作用。我们观察到FLZ阻断Drp1，抑制Drp1酶活性，并减少培养神经元中过度的线粒体分裂。此外，通过抑制线粒体分裂和活性氧生成，FLZ改善了线粒体完整性和膜电位，从而产生神经保护作用。FLZ减少了MPP暴露引起的原代培养多巴胺能神经元突触分支的减少，减少了异常分裂，恢复了神经元中线粒体的正常分布，并对多巴胺能神经元表现出保护作用。研究结果在MPTP诱导的PD小鼠模型中得到验证。结果显示，FLZ显著降低了PD小鼠中脑Drp1的线粒体易位，进而减少了小鼠黑质神经元中的线粒体碎片化。FLZ还保护了PD小鼠中的多巴胺能神经元，并增加了纹状体中的多巴胺含量，从而改善了小鼠的运动协调能力。这些发现阐明了FLZ在PD中产生神经保护作用的这一新发现机制。
