Selective disruption of mitochondrial thiol redox state in cells and in vivo

Booty, L. M. et al. (2019) Selective disruption of mitochondrial thiol redox state in cells and in vivo. Cell Chemical Biology, 26(3), 449-461.e8. (doi: 10.1016/j.chembiol.2018.12.002) (PMID:30713096) (PMCID:PMC6436940)

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Mitochondrial glutathione (GSH) and thioredoxin (Trx) systems function independently of the rest of the cell. While maintenance of mitochondrial thiol redox state is thought vital for cell survival, this was not testable due to the difficulty of manipulating the organelle's thiol systems independently of those in other cell compartments. To overcome this constraint we modified the glutathione S-transferase substrate and Trx reductase (TrxR) inhibitor, 1-chloro-2,4-dinitrobenzene (CDNB) by conjugation to the mitochondria-targeting triphenylphosphonium cation. The result, MitoCDNB, is taken up by mitochondria where it selectively depletes the mitochondrial GSH pool, catalyzed by glutathione S-transferases, and directly inhibits mitochondrial TrxR2 and peroxiredoxin 3, a peroxidase. Importantly, MitoCDNB inactivates mitochondrial thiol redox homeostasis in isolated cells and in vivo, without affecting that of the cytosol. Consequently, MitoCDNB enables assessment of the biomedical importance of mitochondrial thiol homeostasis in reactive oxygen species production, organelle dynamics, redox signaling, and cell death in cells and in vivo.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Caldwell, Dr Stuart and Hartley, Professor Richard
Authors: Booty, L. M., Gawel, J. M., Cvetko, F., Caldwell, S. T., Hall, A. R., Mulvey, J. F., James, A. M., Hinchy, E. C., Prime, T. A., Arndt, S., Beninca, C., Bright, T. P., Clatworthy, M. R., Ferdinand, J. R., Prag, H. A., Logan, A., Prudent, J., Krieg, T., Hartley, R. C., and Murphy, M. P.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Cell Chemical Biology
Publisher:Elsevier (Cell Press)
ISSN (Online):2451-9456
Published Online:31 January 2019
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Cell Chemical Biology 26(3): 449-461.e8
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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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
710821'Exploring mitochondrial metabolism in health and disease using targeted biological chemistryRichard HartleyWellcome Trust (WELLCOTR)110158/Z/15/ZCHEM - CHEMISTRY