Selective mitochondrial superoxide generation in vivo is cardioprotective through hormesis

Salvatore Antonucci,John F Mulvey,Nils Burger,Moises Di Sante,Andrew R Hall,Elizabeth C Hinchy,Stuart T Caldwell,Anja V Gruszczyk,Soni Deshwal,Richard C Hartley,Nina Kaludercic,Michael P Murphy,Fabio Di Lisa,Thomas Krieg

doi:10.1016/j.freeradbiomed.2019.01.034

Abstract

Reactive oxygen species (ROS) have an equivocal role in myocardial ischaemia reperfusion injury. Within the cardiomyocyte, mitochondria are both a major source and target of ROS. We evaluate the effects of a selective, dose-dependent increase in mitochondrial ROS levels on cardiac physiology using the mitochondria-targeted redox cycler MitoParaquat (MitoPQ). Low levels of ROS decrease the susceptibility of neonatal rat ventricular myocytes (NRVMs) to anoxia/reoxygenation injury and also cause profound protection in an in vivo mouse model of ischaemia/reperfusion. However higher doses of MitoPQ resulted in a progressive alteration of intracellular [Ca2+] homeostasis and mitochondrial function in vitro, leading to dysfunction and death at high doses. Our data show that a primary increase in mitochondrial ROS can alter cellular function, and support a hormetic model in which low levels of ROS are cardioprotective while higher levels of ROS are cardiotoxic.

Highlights

Ischaemia/reperfusion (I/R) injury occurs when the blood supply to a region of tissue is disrupted and later restored
3.1 MitoPQ induces a primary increase in mitochondrial Reactive oxygen species (ROS) levels in a dose-dependent manner
MitoTracker Red (MTR) presents some limitations due to its relative lack of sensitivity and specificity, that its accumulation depends on cell and mitochondrial membrane potential (ΔΨm), and these can be affected by different treatments independently of ROS formation

Summary

Introduction

Ischaemia/reperfusion (I/R) injury occurs when the blood supply to a region of tissue is disrupted and later restored. Key to the development of the pathology is a lack of oxygen for oxidative phosphorylation within mitochondria This results in the arrest of forward electron flow in the respiratory chain (Di Lisa et al, 1998) due to the lack of oxygen to act as the terminal electron acceptor. Succinate is accumulated during ischaemia by the reduction of fumarate at mitochondrial complex II (Chouchani et al, 2014), or from anaplerotic supply of glutamate to the tricarboxylic acid cycle leading to succinate that cannot be oxidized due to the reduced Coenzyme Q pool (Zhang et al, 2018). The sustained opening of the mitochondrial permeability transition pore (mPTP), a key arbiter of cell fate, results in significant ROS production. As ROS are among the factors contributing to prolonged mPTP opening there is a positive feedback loop of ROS-induced ROS release (Zorov et al, 2014) through which ROS generation results in sustained mitochondrial dysfunction and eventually cell death (Di Lisa et al, 2011)

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Conclusion