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Inhibition of respiratory Complex I by copper(ii)-bis(thiosemicarbazonato) complexes

Djoko, Karrera Y.; Donnelly, Paul S.; McEwan, Alastair G.


Paul S. Donnelly

Alastair G. McEwan


Several copper(II) complexes of bis(thiosemicarbazones) [Cu(btsc)s] show promise as therapeutics for the treatment of neurological diseases, cancers and bacterial infections. These complexes are thought to act primarily as copper ionophores or “copper boosting” agents, whereby the CuII centre is reduced by cytosolic reductants and CuI is released as “free” or “bioavailable” ion. It is then assumed that the dissociated CuI ion is the species responsible for many of the observed biological effects of Cu(btsc)s. We recently showed that Cu(btsc) complexes inhibited NADH dehydrogenases in the bacterial respiratory chain. In this work, we demonstrate that Cu(btsc) complexes also inhibit mitochondrial respiration and that Complex I in the mitochondrial electron transport chain is a specific target of inhibition. However, bioavailable Cu ions do not appear to contribute to the action of Cu(btsc) as a respiratory inhibitor. Instead, an intact Cu(btsc) molecule may bind reversibly and competitively to the site of ubiquinone binding in Complex I. Our results add to the growing body of evidence that the intact complex may be important in the overall cellular activity of Cu(btsc) complexes and further the understanding of their biological effects as a potential therapeutic.


Djoko, K. Y., Donnelly, P. S., & McEwan, A. G. (2014). Inhibition of respiratory Complex I by copper(ii)-bis(thiosemicarbazonato) complexes. Metallomics, 6(12), 2250-2259.

Journal Article Type Article
Acceptance Date Oct 7, 2014
Online Publication Date Oct 7, 2014
Publication Date 2014-12
Deposit Date Sep 6, 2017
Journal Metallomics
Print ISSN 1756-5901
Electronic ISSN 1756-591X
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 6
Issue 12
Pages 2250-2259