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

Paul S. Donnelly, Jeffrey R. Liddell, SinChun Lim, Brett M. Paterson, Michael A. Cater, Maria S. Savva, Alexandra I. Mot, Janine L. James, Ian A. Trounce, Anthony R. White, Peter J. Crouch

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Abstract

Radiolabeled diacetylbis(4-methylthiosemicarbazonato)copper II[Cu II(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 Cu II(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 Cu II(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 Cu II(atsm). By transfecting the cells with a metal-responsive element reporter construct the increase in Cu retention was shown to involve a Cu II(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 Cu II(atsm). Using these cell culture models our data demonstrate that compromised ETC function, due to the absence of O 2as the terminal electron acceptor or dysfunction of individual components of the ETC, is an important determinant in driving the intracellular dissociation of Cu II(atsm) that increases cellular retention of the Cu.

Original languageEnglish
Pages (from-to)47-52
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number1
DOIs
Publication statusPublished - 3 Jan 2012
Externally publishedYes

Keywords

  • Energy metabolism
  • Radiopharmaceutical
  • Sodium arsenite

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