Modulation of F0F1-ATP Synthase Activity by Cyclophilin D Regulates Matrix Adenine Nucleotide Levels

FEBS J. 2011 Apr;278(7):1112-25. doi: 10.1111/j.1742-4658.2011.08026.x. Epub 2011 Feb 23.


Cyclophilin D was recently shown to bind to and decrease the activity of F(0)F(1)-ATP synthase in submitochondrial particles and permeabilized mitochondria [Giorgio V et al. (2009) J Biol Chem, 284, 33982-33988]. Cyclophilin D binding decreased both ATP synthesis and hydrolysis rates. In the present study, we reaffirm these findings by demonstrating that, in intact mouse liver mitochondria energized by ATP, the absence of cyclophilin D or the presence of cyclosporin A led to a decrease in the extent of uncoupler-induced depolarization. Accordingly, in substrate-energized mitochondria, an increase in F(0)F(1)-ATP synthase activity mediated by a relief of inhibition by cyclophilin D was evident in the form of slightly increased respiration rates during arsenolysis. However, the modulation of F(0)F(1)-ATP synthase by cyclophilin D did not increase the adenine nucleotide translocase (ANT)-mediated ATP efflux rate in energized mitochondria or the ATP influx rate in de-energized mitochondria. The lack of an effect of cyclophilin D on the ANT-mediated adenine nucleotide exchange rate was attributed to the ∼ 2.2-fold lower flux control coefficient of the F(0)F(1)-ATP synthase than that of ANT, as deduced from measurements of adenine nucleotide flux rates in intact mitochondria. These findings were further supported by a recent kinetic model of the mitochondrial phosphorylation system, suggesting that an ∼ 30% change in F(0)F(1)-ATP synthase activity in fully energized or fully de-energized mitochondria affects the ADP-ATP exchange rate mediated by the ANT in the range 1.38-1.7%. We conclude that, in mitochondria exhibiting intact inner membranes, the absence of cyclophilin D or the inhibition of its binding to F(0)F(1)-ATP synthase by cyclosporin A will affect only matrix adenine nucleotides levels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine Nucleotides / metabolism*
  • Adenosine Diphosphate / metabolism
  • Animals
  • Arsenates / pharmacology
  • Cell Respiration / drug effects
  • Cell Respiration / physiology
  • Cyclophilin D
  • Cyclophilins / metabolism*
  • Cyclosporine / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Herbicides / pharmacology
  • Hydrogen-Ion Concentration
  • Magnesium / metabolism
  • Membrane Potential, Mitochondrial
  • Mice
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / metabolism*
  • Mitochondria, Liver / ultrastructure
  • Models, Biological
  • Oxygen Consumption
  • Proton-Translocating ATPases / metabolism*
  • Protons


  • Adenine Nucleotides
  • Arsenates
  • Cyclophilin D
  • Enzyme Inhibitors
  • Herbicides
  • PPIF protein, mouse
  • Protons
  • Adenosine Diphosphate
  • Cyclosporine
  • Proton-Translocating ATPases
  • Cyclophilins
  • Magnesium
  • arsenic acid