Activated macrophages utilize glycolytic ATP to maintain mitochondrial membrane potential and prevent apoptotic cell death

Salvador Moncada (1) , Samantha O. Henderson (1) , Assegid Garedew (1)

1 WIBR - Wolfson Institute for Biomedical Research

We have previously investigated the bioenergetic consequences of activating J774.A1 macrophages (MФ) with interferon (IFN)γ and lipopolysaccharide (LPS) and found that there is a nitric oxide (NO)-dependent mitochondrial impairment and stabilization of hypoxia inducible factor (HIF)-1α, which synergize to activate glycolysis and generate large quantities of ATP. We now demonstrate, using TMRM fluorescence and time-lapse confocal microscopy, that these cells maintain a high mitochondrial membrane potential (ΔΨm) despite the complete inhibition of respiration. The maintenance of high ΔΨm is due to the utilization 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 MФ with inhibitors of either of these enzymes, but not with inhibitors of the respiratory chain complexes I to IV, led to a collapse in ΔΨm and to an immediate increase in intracellular [ATP], due to the prevention of ATP hydrolysis by the FoF1-ATPase. This collapse in ΔΨm was followed by activation of caspase 9 and 3 and subsequent apoptotic cell death. Our results indicate that during inflammatory activation "glycolytically competent cells" such as MФ utilize significant amounts of the glycolytically-generated ATP to maintain ΔΨm and thereby prevent apoptosis

Mots clés: Macrophage activation; mitochondria; apoptosis; ΔΨm; caspase activation

Salvador Moncada, Samantha O. Henderson, Assegid Garedew. Activated macrophages utilize glycolytic ATP to maintain mitochondrial membrane potential and prevent apoptotic cell death. Cell Death and Differentiation, 2010, n/a (n/a), pp.n/a-n/a. ⟨10.1038/cdd.2010.27⟩. ⟨hal-00521163⟩