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

C. Chinopoulos, Csaba Konràd, Gergely Kiss, Eugeniy Metelkin, B. Törőcsik, Steven F. Zhang, Anatoly A. Starkov

Research output: Contribution to journalArticle

32 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 2011

Fingerprint

Adenine Nucleotides
Mitochondria
Adenosine Triphosphate
Modulation
ATP Translocases Mitochondrial ADP
Cyclosporine
cyclophilin D
Submitochondrial Particles
Fluxes
Glycogen Synthase
Phosphorylation
Liver Mitochondrion
Depolarization
Respiratory Rate
Liver
Adenosine Diphosphate
Hydrolysis
Membranes

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Modulation of F0F1-ATP synthase activity by cyclophilin D regulates matrix adenine nucleotide levels. / Chinopoulos, C.; Konràd, Csaba; Kiss, Gergely; Metelkin, Eugeniy; Törőcsik, B.; Zhang, Steven F.; Starkov, Anatoly A.

In: FEBS Journal, Vol. 278, No. 7, 04.2011, p. 1112-1125.

Research output: Contribution to journalArticle

Chinopoulos, C. ; Konràd, Csaba ; Kiss, Gergely ; Metelkin, Eugeniy ; Törőcsik, B. ; Zhang, Steven F. ; Starkov, Anatoly A. / Modulation of F0F1-ATP synthase activity by cyclophilin D regulates matrix adenine nucleotide levels. In: FEBS Journal. 2011 ; Vol. 278, No. 7. pp. 1112-1125.
@article{2e2866b0d6164213898811717ba6311d,
title = "Modulation of F0F1-ATP synthase activity by cyclophilin D regulates matrix adenine nucleotide levels",
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.",
keywords = "adenine nucleotide carrier, control strength, metabolic control analysis, permeability transition pore, phosphate carrier",
author = "C. Chinopoulos and Csaba Konr{\`a}d and Gergely Kiss and Eugeniy Metelkin and B. T{\"o}rőcsik and Zhang, {Steven F.} and Starkov, {Anatoly A.}",
year = "2011",
month = "4",
doi = "10.1111/j.1742-4658.2011.08026.x",
language = "English",
volume = "278",
pages = "1112--1125",
journal = "FEBS Journal",
issn = "1742-464X",
publisher = "Wiley-Blackwell",
number = "7",

}

TY - JOUR

T1 - Modulation of F0F1-ATP synthase activity by cyclophilin D regulates matrix adenine nucleotide levels

AU - Chinopoulos, C.

AU - Konràd, Csaba

AU - Kiss, Gergely

AU - Metelkin, Eugeniy

AU - Törőcsik, B.

AU - Zhang, Steven F.

AU - Starkov, Anatoly A.

PY - 2011/4

Y1 - 2011/4

N2 - 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.

AB - 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.

KW - adenine nucleotide carrier

KW - control strength

KW - metabolic control analysis

KW - permeability transition pore

KW - phosphate carrier

UR - http://www.scopus.com/inward/record.url?scp=79952837890&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952837890&partnerID=8YFLogxK

U2 - 10.1111/j.1742-4658.2011.08026.x

DO - 10.1111/j.1742-4658.2011.08026.x

M3 - Article

C2 - 21281446

AN - SCOPUS:79952837890

VL - 278

SP - 1112

EP - 1125

JO - FEBS Journal

JF - FEBS Journal

SN - 1742-464X

IS - 7

ER -