Modulation of F0F1-ATP synthase activity by cyclophilin D regulates matrix adenine nucleotide levels

Christos Chinopoulos, Csaba Konràd, Gergely Kiss, Eugeniy Metelkin, Beata Töröcsik, Steven F. Zhang, Anatoly A. Starkov

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Cyclophilin D was recently shown to bind to and decrease the activity of F0F1-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 F0F1-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 F0F1-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 0F1-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 0F1-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 F0F1-ATP synthase by cyclosporin A will affect only matrix adenine nucleotides levels.

Original languageEnglish
Pages (from-to)1112-1125
Number of pages14
JournalFEBS Journal
Volume278
Issue number7
DOIs
Publication statusPublished - Apr 1 2011

Keywords

  • adenine nucleotide carrier
  • control strength
  • metabolic control analysis
  • permeability transition pore
  • phosphate carrier

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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