Data_Sheet_1_Zika Virus-Induced Neuronal Apoptosis via Increased Mitochondrial Fragmentation.docx

The 2015 to 2016 outbreak of Zika virus (ZIKV) infections in the Americas coincided with a dramatic increase in neurodevelopmental abnormalities, including fetal microcephaly, in newborns born to infected women. In this study, we observed mitochondrial fragmentation and disrupted mitochondrial membrane potential after 24 h of ZIKV infection in human neural stem cells and the SNB-19 glioblastoma cell line. The severity of these changes correlated with the amount of ZIKV proteins expressed in infected cells. ZIKV infection also decreased the levels of mitofusin 2, which modulates mitochondria fusion. Mitochondrial division inhibitor 1 (Mdivi-1), a small molecule inhibiting mitochondria fission, ameliorated mitochondria disruptions and reduced cell death in ZIKV-infected cells. Collectively, this study suggests that abnormal mitochondrial fragmentation contributes to ZIKV-induced neuronal cell death; rebalancing mitochondrial dynamics of fission-fusion could be a therapeutic strategy for drug development to treat ZIKV-mediated neuronal apoptosis.

2015至2016年美洲暴发的寨卡病毒（Zika virus, ZIKV）感染疫情，与感染孕妇所产新生儿出现的包括胎儿小头畸形在内的神经发育异常病例大幅增加同期发生。本研究观察到，在人类神经干细胞与SNB-19胶质母细胞瘤细胞系中，寨卡病毒感染24小时后会引发线粒体碎片化及线粒体膜电位受损。上述变化的严重程度与感染细胞内寨卡病毒蛋白的表达量呈正相关。寨卡病毒感染还会下调线粒体融合蛋白2（Mitofusin 2）的表达水平，该蛋白可调控线粒体融合过程。线粒体分裂抑制剂1（Mdivi-1）作为一种抑制线粒体分裂的小分子化合物，可改善寨卡病毒感染细胞中的线粒体紊乱并减少细胞死亡。综上，本研究表明异常线粒体碎片化参与介导寨卡病毒诱导的神经元细胞死亡；重平衡线粒体分裂与融合的动态平衡，或可成为开发治疗寨卡病毒介导神经元凋亡药物的潜在治疗策略。