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An impaired mitochondrial electron transport chain increases retention of the hypoxia imaging agent diacetylbis(4-methylthiosemicarbazonato)copper II

Donnelly, Paul S., Liddell, Jeffrey R., Lim, SinChun, Paterson, Brett M., Cater, Michael A., Savva, Maria S., Mot, Alexandra I., James, Janine L., Trounce, Ian A., White, Anthony R. and Crouch, Peter J. 2012, An impaired mitochondrial electron transport chain increases retention of the hypoxia imaging agent diacetylbis(4-methylthiosemicarbazonato)copper II, Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 1, pp. 47-52, doi: 10.1073/pnas.1116227108.

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Title An impaired mitochondrial electron transport chain increases retention of the hypoxia imaging agent diacetylbis(4-methylthiosemicarbazonato)copper II
Formatted title An impaired mitochondrial electron transport chain increases retention of the hypoxia imaging agent diacetylbis(4-methylthiosemicarbazonato)copperII
Author(s) Donnelly, Paul S.
Liddell, Jeffrey R.
Lim, SinChun
Paterson, Brett M.
Cater, Michael A.
Savva, Maria S.
Mot, Alexandra I.
James, Janine L.
Trounce, Ian A.
White, Anthony R.
Crouch, Peter J.
Journal name Proceedings of the National Academy of Sciences of the United States of America
Volume number 109
Issue number 1
Start page 47
End page 52
Total pages 6
Publisher National Academy of Sciences
Place of publication Washington, D.C.
Publication date 2012-01-03
ISSN 0027-8424
1091-6490
Summary Radiolabeled diacetylbis(4-methylthiosemicarbazonato)copperII [CuII(atsm)] is an effective positron-emission tomography imaging agent for myocardial ischemia, hypoxic tumors, and brain disorders with regionalized oxidative stress, such as mitochondrial myopathy, encephalopathy, and lactic acidosis with stroke-like episodes (MELAS) and Parkinson’s disease. An excessively elevated reductive state is common to these conditions and has been proposed as an important mechanism affecting cellular retention of Cu from CuII(atsm). However, data from whole-cell models to demonstrate this mechanism have not yet been provided. The present study used a unique cell culture model, mitochondrial xenocybrids, to provide whole-cell mechanistic data on cellular retention of Cu from CuII(atsm). Genetic incompatibility between nuclear and mitochondrial encoded subunits of the mitochondrial electron transport chain (ETC) in xenocybrid cells compromises normal function of the ETC. As a consequence of this impairment to the ETC we show xenocybrid cells upregulate glycolytic ATP production and accumulate NADH. Compared to control cells the xenocybrid cells retained more Cu after being treated with CuII(atsm). By transfecting the cells with a metal-responsive element reporter construct the increase in Cu retention was shown to involve a CuII(atsm)-induced increase in intracellular bioavailable Cu specifically within the xenocybrid cells. Parallel experiments using cells grown under hypoxic conditions confirmed that a compromised ETC and elevated NADH levels contribute to increased cellular retention of Cu from CuII(atsm). Using these cell culture models our data demonstrate that compromised ETC function, due to the absence of O2 as the terminal electron acceptor or dysfunction of individual components of the ETC, is an important determinant in driving the intracellular dissociation of CuII(atsm) that increases cellular retention of the Cu.
Language eng
DOI 10.1073/pnas.1116227108
Field of Research 060199 Biochemistry and Cell Biology not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2012, National Academy of Sciences
Persistent URL http://hdl.handle.net/10536/DRO/DU:30052473

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Created: Mon, 13 May 2013, 17:10:32 EST by Teresa Treffry

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