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

A Garedew1, S O Henderson, S Moncada

  • 1Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.

Cell Death and Differentiation
|March 27, 2010
PubMed

Insights

Activated macrophages use energy from glycolysis to maintain mitochondrial function and prevent cell death. This involves reverse ATP synthase and ANT activity, crucial for survival during inflammation.

Area of Science:

  • Cellular Biology
  • Immunology
  • Bioenergetics

Background:

  • Macrophages (MΦ) activated with interferon-γ (IFN-γ) and lipopolysaccharide (LPS) exhibit nitric oxide (NO)-dependent mitochondrial impairment and hypoxia-inducible factor (HIF)-1α stabilization.
  • This leads to enhanced glycolysis and ATP production, but the role of mitochondrial membrane potential (ΔΨ(m)) in this context was unclear.

Purpose of the Study:

  • To investigate the bioenergetic mechanisms underlying the survival of activated macrophages despite impaired respiration.
  • To determine the role of mitochondrial membrane potential (ΔΨ(m)) maintenance in preventing apoptosis in these cells.

Main Methods:

  • Tetramethylrhodamine methyl ester (TMRM) fluorescence and time-lapse confocal microscopy were employed.
  • The effects of inhibitors targeting F(o)F(1)-ATP synthase and adenine nucleotide translocase (ANT) were assessed.
  • Apoptosis markers including Bax translocation, cytochrome c release, and caspase activation were analyzed.

Main Results:

  • Activated macrophages maintain a high ΔΨ(m) even with inhibited respiration, utilizing glycolytically generated ATP.
  • Reverse functioning of F(o)F(1)-ATP synthase and ANT is essential for maintaining this ΔΨ(m).
  • Inhibiting these enzymes, but not respiratory chain complexes, caused ΔΨ(m) collapse, increased intracellular ATP, and triggered apoptosis.

Conclusions:

  • Glycolytically competent cells, like activated macrophages, employ a significant portion of glycolytic ATP to sustain ΔΨ(m) as an anti-apoptotic mechanism.
  • This ATP-dependent process is critical for cell survival during inflammatory responses.

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