Journal
CELL DEATH AND DIFFERENTIATION
Volume 17, Issue 10, Pages 1540-1550Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2010.27
Keywords
macrophage activation; Delta Psi(m); glycolysis; oxidative phosphorylation; apoptosis; caspase activation
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We have previously analysed the bioenergetic consequences of activating J774.A1 macrophages (MU) with interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS) and found that there is a nitric oxide (NO)-dependent mitochondrial impairment and stabilization of hypoxia-inducible factor (HIF)-1 alpha, which synergize to activate glycolysis and generate large quantities of ATP. We now show, using tetramethylrhodamine methyl ester (TMRM) fluorescence and time-lapse confocal microscopy, that these cells maintain a high mitochondrial membrane potential (Delta Psi m) despite the complete inhibition of respiration. The maintenance of high Delta Psi m is due to the use of a significant proportion of glycolytically generated ATP as a defence mechanism against cell death. This is achieved by the reverse functioning of FoF1-ATP synthase and adenine nucleotide translocase (ANT). Treatment of activated MU with inhibitors of either of these enzymes, but not with inhibitors of the respiratory chain complexes I to IV, led to a collapse in Delta Psi m and to an immediate increase in intracellular [ATP], due to the prevention of ATP hydrolysis by the FoF1-ATP synthase. This collapse in Delta Psi m was followed by translocation of Bax from cytosol to the mitochondria, release of cytochrome c into the cytosol, activation of caspases 3 and 9 and subsequent apoptotic cell death. Our results indicate that during inflammatory activation 'glycolytically competent cells' such as MU use significant amounts of the glycolytically generated ATP to maintain Delta Psi m and thereby prevent apoptosis. Cell Death and Differentiation (2010) 17, 1540-1550; doi:10.1038/cdd.2010.27; published online 26 March 2010
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