Selective mitochondrial superoxide generation in vivo is cardioprotective through hormesis

Antonucci, S. et al. (2019) Selective mitochondrial superoxide generation in vivo is cardioprotective through hormesis. Free Radical Biology and Medicine, 134, pp. 678-687. (doi:10.1016/j.freeradbiomed.2019.01.034) (PMID:30731114)

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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.

Item Type:Articles
Additional Information:The work is supported by an MRC Studentship to JFM and a Wellcome Trust Investigator award to RCH (110158/Z/15/Z), the Leducq Transatlantic Network of Excellence, the COST Action EU-CARDIOPROTECTION CA16225,and the University of Padova Strategico grant (FDL). Part of the study was funded by an MRC Project Grant to TK(MR/P000320/1).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Caldwell, Dr Stuart and Hartley, Professor Richard
Authors: Antonucci, S., Mulvey, J. F., Burger, N., Di Sante, M., Hall, A. R., Hinchy, E. C., Caldwell, S., Gruszczyk, A. V., Deshwal, S., Hartley, R. C., Kaludercic, N., Murphy, M. P., Di Lisa, F., and Krieg, T.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Free Radical Biology and Medicine
Publisher:Elsevier
ISSN:0891-5849
ISSN (Online):0891-5849
Published Online:04 February 2019
Copyright Holders:Copyright © 2019 Elsevier
First Published:First published in Free Radical Biology and Medicine 134:678-687
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
710821'Exploring mitochondrial metabolism in health and disease using targeted biological chemistryRichard HartleyWellcome Trust (WELLCOTR)110158/Z/15/ZCHEM - CHEMISTRY