Zinc causes the death of hypoxic astrocytes by inducing ROS production through mitochondria dysfunction

Rong Pan,Zhifeng Qi,Ke Jian Liu

doi:10.1007/s41048-019-00098-3

Abstract

Cerebral ischemia triggers a cascade of events that contribute to ischemic brain damages. Zinc release and accumulation has been shown to lead to brain cell death following cerebral ischemia. However, the mechanism underlying remains to be elucidated. Our recently published work showed that suppression of mitochondrial-derived reactive oxygen species (ROS) production significantly reduced ischemic stroke related brain damage within 6 h. Herein, we investigated the relationship between zinc accumulation and mitochondrial-derived ROS production in astrocytes after 3-h hypoxia. We found that inhibition of mitochondrial-derived ROS significantly decreased total amount of ROS generation and cell death in primary astrocytes during hypoxia when zinc was overload. In contrast, the inhibition of NADPH oxidase-derived ROS had less of an effect. Our results also showed that zinc and mitochondria were colocalized in hypoxic astrocytes. Moreover, extracellular zinc addition caused zinc accumulation in the mitochondria and decreased mitochondrial membrane potential, leading to mitochondria dysfunction. These findings provide a novel mechanism that zinc accumulation contributes to hypoxia-induced astrocytes death by disrupting mitochondria function, following cerebral ischemia.

Highlights

Zinc is essential for cerebral development, which plays a signaling role in the central nerve system (Bitanihirwe and Cunningham 2009)
It suggests that astrocytes are more vulnerable by hypoxia and neurons have been protected by astrocytes under hypoxia
The present study investigated the interaction between zinc and reactive oxygen species (ROS) in acute hypoxic astrocytes, and explored the relationship of zinc accumulation and mitochondria dysfunction

Summary

Introduction

Zinc is essential for cerebral development, which plays a signaling role in the central nerve system (Bitanihirwe and Cunningham 2009). ROS are generated through multiple diverse sources, including NADPH oxidase, mitochondria, cyclooxygenase, and monoamine oxygenase (Abramov et al 2007; Adibhatla and Hatcher 2010; Yang et al 2018). Among these sources, NADPH oxidase has been considered as a major pathway to generate neuronal ROS, which causes cell death in hypoglycemia as well as in anoxia and reoxygenation (Abramov et al 2007). We recently reported that suppressing the production of mitochondrial-derived ROS by mitochondria-targeted ROS inhibitor R(?) pramipexole [R(?) PPX] significantly reduced brain damage at 6 h after the cerebral ischemia onset (Zhao et al 2018b)

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Conclusion