Selective superoxide generation within mitochondria by the targeted redox cycler MitoParaquat

Robb, E. L. et al. (2015) Selective superoxide generation within mitochondria by the targeted redox cycler MitoParaquat. Free Radical Biology and Medicine, 89, pp. 883-894. (doi:10.1016/j.freeradbiomed.2015.08.021) (PMID:26454075)

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Abstract

Superoxide is the proximal reactive oxygen species (ROS) produced by the mitochondrial respiratory chain and plays a major role in pathological oxidative stress and redox signaling. While there are tools to detect or decrease mitochondrial superoxide, none can rapidly and specifically increase superoxide production within the mitochondrial matrix. This lack impedes progress, making it challenging to assess accurately the roles of mitochondrial superoxide in cells and in vivo. To address this unmet need, we synthesized and characterized a mitochondria-targeted redox cycler, MitoParaquat (MitoPQ) that comprises a triphenylphosphonium lipophilic cation conjugated to the redox cycler paraquat. MitoPQ accumulates selectively in the mitochondrial matrix driven by the membrane potential. Within the matrix, MitoPQ produces superoxide by redox cycling at the flavin site of complex I, selectively increasing superoxide production within mitochondria. MitoPQ increased mitochondrial superoxide in isolated mitochondria and cells in culture ~a thousand-fold more effectively than untargeted paraquat. MitoPQ was also more toxic than paraquat in the isolated perfused heart and in Drosophila in vivo. MitoPQ enables the selective generation of superoxide within mitochondria and is a useful tool to investigate the many roles of mitochondrial superoxide in pathology and redox signaling in cells and in vivo.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Senn, Dr Hans and Hartley, Professor Richard
Authors: Robb, E. L., Gawel, J. M., Aksentijević, D., Cocheme, H. M., Stewart, T. S., Shchepinova, M. M., Qiang, H., Prime, T. A., Bright, T. P., James, A. M., Shattock, M. J., Senn, H. M., Hartley, R. C., and Murphy, M. P.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Free Radical Biology and Medicine
Publisher:Elsevier
ISSN:0891-5849
ISSN (Online):1873-4596
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Free Radical Biology and Medicine 89:883-894
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
553931Developing chemical mass spectrometry probes to assess the production of reactive oxygen species in vivoRichard HartleyBiotechnology and Biological Sciences Research Council (BBSRC)BB/I012826/1CHEM - CHEMISTRY
608951Engineering and Physical Sciences Doctoral Training Grant 2012-16Mary Beth KneafseyEngineering & Physical Sciences Research Council (EPSRC)EP/K503058/1VICE PRINCIPAL RESEARCH & ENTERPRISE