Polybrene induces neural degeneration by bidirectional Ca(2+) influx-dependent mitochondrial and ER-mitochondrial dynamics.
Polybrene induces neural degeneration by bidirectional Ca(2+) influx-dependent mitochondrial and ER-mitochondrial dynamics.
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Polybrene 通过双向 Ca2 流入依赖性线粒体和 ER 线粒体动力学诱导神经变性
DOI：
10.1038/s41419-018-1009-8
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发表时间：
2018-09-20
影响因子：
9
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Bao F;Shi H;Gao M;Yang L;Zhou L;Zhao Q;Wu Y;Chen K;Xiang G;Long Q;Guo J;Zhang J;Liu X
溴化己二甲胺（Polybrene）曾在临床上用作肝素中和剂，最近在病毒介导的基因治疗试验和基因转移研究中用作促进剂。然而，迄今为止，低剂量聚凝胺的组织特异性毒性潜力一直被忽视。在这里，我们发现，脑室内（ICV）聚凝胺注射后，小鼠表现出运动障碍，伴随着神经死亡和神经胶质增生的大脑，在人类神经元，聚凝胺诱导浓度依赖性神经炎珠和碎片。从机制上讲，聚凝胺诱导快速电压依赖性钙通道（VDCC）介导的细胞外Ca 2+内流。升高的细胞质Ca 2+激活DRP 1，导致线粒体断裂和代谢功能障碍。同时，Ca 2+内流诱导内质网（ER）断裂，并加强ER与线粒体之间的联系，这使得线粒体易于Ca 2+超载，从而导致通透性转换。这些结果揭示了聚凝胺的意想不到的神经元毒性，其中Ca 2+内流作为线粒体动力学和ER-线粒体重塑的调节剂。
Hexadimethrine bromide (Polybrene) was once used clinically as a heparin neutralizer and has recently found use as a promoter in virus-mediated gene therapy trials and gene transfer in research. However, the potential for tissue-specific toxicity of polybrene at low doses has been ignored so far. Here, we found that after intracerebroventricular (ICV) polybrene injection, mice showed disability of movement accompanied neural death and gliosis in brain, and in human neurons, polybrene induces concentration-dependent neuritic beading and fragmentation. Mechanistically, polybrene induces a rapid voltage-dependent calcium channel (VDCC)-mediated influx of extracellular Ca2+. The elevated cytoplasmic Ca2+ activates DRP1, which leads to mitochondrial fragmentation and metabolic dysfunction. At the same time, Ca2+ influx induces endoplasmic reticulum (ER) fragmentation and tightened associations between ER and mitochondria, which makes mitochondria prone to Ca2+ overloading and ensuing permeability transition. These results reveal an unexpected neuronal toxicity of polybrene, wherein Ca2+ influx serves as a regulator for both mitochondrial dynamics and ER–mitochondrial remodeling.
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