Premium
Modulation of F 0 F 1 ‐ATP synthase activity by cyclophilin D regulates matrix adenine nucleotide levels
Author(s) -
Chinopoulos Christos,
Konràd Csaba,
Kiss Gergely,
Metelkin Eugeniy,
Töröcsik Beata,
Zhang Steven F.,
Starkov Anatoly A.
Publication year - 2011
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2011.08026.x
Subject(s) - atp synthase , submitochondrial particle , cyclophilin , mitochondrion , adenine nucleotide , mitochondrial matrix , biochemistry , adenine nucleotide translocator , biology , atp–adp translocase , nucleotide , atp hydrolysis , adenosine triphosphate , biophysics , enzyme , chemistry , inner mitochondrial membrane , atpase , cytosol , gene
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. Structured digital abstract• F0F1‐ATPase beta and CypD physically interact by cross‐linking study (View interaction)