Mitochondrial superoxide generation induces a parkinsonian phenotype in zebrafish and huntingtin aggregation in human cells

Pinho, B. R., Reis, S. D., Hartley, R. C. , Murphy, M. P. and Oliveira, J. M.A. (2019) Mitochondrial superoxide generation induces a parkinsonian phenotype in zebrafish and huntingtin aggregation in human cells. Free Radical Biology and Medicine, 130, pp. 318-327. (doi:10.1016/j.freeradbiomed.2018.10.446) (PMID:30389496) (PMCID:PMC6340810)

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Abstract

Superoxide generation by mitochondria respiratory complexes is a major source of reactive oxygen species (ROS) which are capable of initiating redox signaling and oxidative damage. Current understanding of the role of mitochondrial ROS in health and disease has been limited by the lack of experimental strategies to selectively induce mitochondrial superoxide production. The recently-developed mitochondria-targeted redox cycler MitoParaquat (MitoPQ) overcomes this limitation, and has proven effective in vitro and in Drosophila. Here we present an in vivo study of MitoPQ in the vertebrate zebrafish model in the context of Parkinson's disease (PD), and in a human cell model of Huntington's disease (HD). We show that MitoPQ is 100-fold more potent than non-targeted paraquat in both cells and in zebrafish in vivo. Treatment with MitoPQ induced a parkinsonian phenotype in zebrafish larvae, with decreased sensorimotor reflexes, spontaneous movement and brain tyrosine hydroxylase (TH) levels, without detectable effects on heart rate or atrioventricular coordination. Motor phenotypes and TH levels were partly rescued with antioxidant or monoaminergic potentiation strategies. In a HD cell model, MitoPQ promoted mutant huntingtin aggregation without increasing cell death, contrasting with the complex I inhibitor rotenone that increased death in cells expressing either wild-type or mutant huntingtin. These results show that MitoPQ is a valuable tool for cellular and in vivo studies of the role of mitochondrial superoxide generation in redox biology, and as a trigger or co-stressor to model metabolic and neurodegenerative disease phenotypes.

Item Type:Articles
Additional Information:Work in JMAO's lab was supported by the FCT – Fundação para a Ciência e a Tecnologia, Portugal – (P2020-PTDC/NEU-NMC/0412/2014; 3599-PPCDT; UID/QUI/50006/2013) and the European Union (POCI-01-0145-FEDER-016577). BRP and SDR acknowledge FCT for respective PostDoc (SFRH/BPD/102259/2014) and PhD (PD/BD/113567/2015) fellowships. Work in MPM's lab was supported by the Medical Research Council UK (MC_U105663142) and by a Wellcome Trust Investigator award (110159/Z/15/Z). Work in RCH's lab was supported by a Wellcome Trust Investigator award (110158/Z/15/Z).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Hartley, Professor Richard
Authors: Pinho, B. R., Reis, S. D., Hartley, R. C., Murphy, M. P., and Oliveira, J. M.A.
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
Published Online:31 October 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Free Radical Biology and Medicine 130:318-327
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