Heat stress induced apoptosis is triggered by transcription-independent p53, Ca(2+) dyshomeostasis and the subsequent Bax mitochondrial translocation.

Z T Gu,M Zhao,F Wu,L Li,Y Geng,P Zhao,L Su,Y S Liu,H Yang

doi:10.1038/srep11497

Abstract

In this study, We demonstrated that Bax mitochondrial translocation plays a vital role in the initiation of the mitochondrial signaling pathway upon activation by heat stress. In addition, both p53 mitochondrial translocation and Ca2+ signal mediated MPTP opening activate Bax mitochondrial translocation. Employing pifithrin-α (a p53 mitochondrial translocation inhibitor) and CsA (a permeability transition pore (MPTP) inhibitor), we found that heat stress induced Bax mitochondrial translocation was significantly inhibited in cells pretreated with both PFT and CsA. Furthermore, we demonstrated that generation of reactive oxygen species (ROS) is a critical mediator in heat stress induced apoptosis and that the antioxidant MnTBAP significantly decreased heat stress induced p53 mitochondrial translocation and Ca2+ signal mediated MPTP opening, as well as the subsequent Bax mitochondrial translocation and activation of the caspase cascade. Taken together, our results indicate that heat stress induces apoptosis through the mitochondrial pathway with ROS dependent mitochondrial p53 translocation and Ca2+ dyshomeostasis, and the ensuing intro Bax mitochondrial translocation as the upstream events involved in triggering the apoptotic process observed upon cellular exposure to heat stress.

Highlights

In heat stroke, the molecular mechanism by which heat stress induces endothelial-cell apoptosis is still poorly understood
Cell viability was found to have declined drastically and plasma membrane integrity was damaged significantly in a time-dependent manner after exposure to heat stress. These results suggest that heat stress exerts a cytotoxic effect on Human umbilical vein endothelial cells (HUVECs) cells
We demonstrated that conformational change and mitochondrial translocation of Bax play a vital role in heat stress induced apoptosis

Summary

Introduction

In heat stroke, the molecular mechanism by which heat stress induces endothelial-cell apoptosis is still poorly understood. The chronology of cellular events that initiates calcium dyshomeostasis and increase in oxidative stress, which lead to the endothelial cell death observed in heat stress condition remains unknown. It has been well established that intracellular Ca2+ overload can induce cytotoxicity and trigger apoptotic cell death through activating two pathways, the mitochondria dependent and independent pathways[13]. We focused on two intracellular events, 1) heat stress induced p53 translocation to mitochondria, which in turn induces the mitochondrial apoptotic pathways[12] and 2) heat stress induced calcium mobilization, mitochondrial calcium overload and the subsequent mitochondria dependent cell death cascade in HUVEC cells. We demonstrated that Bax conformational change and mitochondrial translocation are the key events that link heat stress induced apoptosis to the increased ROS that acts as an upstream signal triggering the mitochondrial apoptotic pathways

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Results

Conclusion