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

• DOI: 10.1073/pnas.1116227108
• Publication Date: 2011-12-16T06:26:42Z
• Authors: 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
• Keywords: Lactic acidosis; Hypoxia; Mitochondrial matrix

Radiolabeled diacetylbis(4-methylthiosemicarbazonato)copper II [Cu (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, lactic acidosis stroke-like episodes (MELAS) Parkinson’s disease. An excessively elevated reductive state common to these conditions has been proposed important mechanism affecting cellular retention of Cu from (atsm). However, data whole-cell models demonstrate this have not yet provided. The present study used a unique cell culture model, xenocybrids, provide mechanistic on Genetic incompatibility between nuclear encoded subunits the electron transport chain (ETC) in xenocybrid cells compromises normal function ETC. As consequence impairment ETC we show upregulate glycolytic ATP production accumulate NADH. Compared control retained more after being treated By transfecting metal-responsive element reporter construct increase was shown involve (atsm)-induced intracellular bioavailable specifically within cells. Parallel experiments using grown under confirmed that compromised NADH levels contribute increased Using our function, due absence O 2 terminal acceptor or dysfunction individual components ETC, determinant driving dissociation (atsm) increases Cu.