Polybrene induces neural degeneration by bidirectional Ca2+ influx-dependent mitochondrial and ER\u2013mitochondrial dynamics

Feixiang Bao,Keshi Chen,Qi Long,Lingyan Zhou,Jian Zhang,Xingguo Liu,Jingyi Guo,Ge Xiang,Qiuge Zhao,Mi Gao,Hongyan Shi,Liang Yang,Yi Wu

doi:10.1038/s41419-018-1009-8

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.

Highlights

Polybrene, a quaternary ammonium salt, was firstly introduced into clinical practice as a heparin neutralizer[1]
Mice treated with polybrene showed disability in movement at day 3 after polybrene injection in comparison to mice treated with saline as assayed by the Rotating Rod test
We investigated the effects of polybrene on human neurons in vitro using induced pluripotent stem cell-differentiated neuron system

Summary

Introduction

A quaternary ammonium salt, was firstly introduced into clinical practice as a heparin neutralizer[1]. Heparin was the mainstay in the treatment and prevention of thrombosis in such diverse clinical settings as venous thromboembolism, acute coronary syndrome. Toxic stresses could trigger neuritic degeneration, which is a common and early feature of disorders of the nervous. Official journal of the Cell Death Differentiation Association. Bao et al Cell Death and Disease (2018)9:966 system. Mitochondrial Ca2+ overload triggers an injury response through opening the mitochondrial permeability transition pore (mPTP), which leads to the loss of Δψm[22,23,24]. Under apoptosis-inducing conditions, tightened endoplasmic reticulum (ER) and mitochondria connections were observed to make mitochondria prone to Ca2+ overloading and ensuing permeability transition[25]

Methods

Results

Conclusion