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Cell Death Dis. 2018 Sep 20;9(10):966. doi: 10.1038/s41419-018-1009-8.

Polybrene induces neural degeneration by bidirectional Ca2+ influx-dependent mitochondrial and ER-mitochondrial dynamics.

Bao F1,2, Shi H1,2,3, Gao M1,2, Yang L1,2, Zhou L1,2, Zhao Q1,2,4, Wu Y1,2, Chen K1,2, Xiang G1,2, Long Q1,2, Guo J1,2, Zhang J1,2, Liu X5,6.

Author information

1
CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangzhou Medical University, Guangzhou, China.
2
Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Hefei Institue of Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Guangzhou, China.
3
Institute of Physical Science and Information Technology, Anhui University, Hefei, China.
4
The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
5
CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangzhou Medical University, Guangzhou, China. liu_xingguo@gibh.ac.cn.
6
Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Hefei Institue of Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Guangzhou, China. liu_xingguo@gibh.ac.cn.

Abstract

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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