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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Abstract
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 |
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Status: | Published |
Refereed: | Yes |
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: | 2451-9456 |
ISSN (Online): | 2451-9448 |
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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