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Regulation of respiration in brain mitochondria and synaptosomes: restrictions of ADP diffusion in situ, roles of tubulin, and mitochondrial creatine kinase

  • Claire Monge
  • Nathalie Beraud
  • Andrey V. Kuznetsov
  • Tatiana Rostovtseva
  • Dan Sackett
  • Uwe Schlattner
  • Marko Vendelin
  • Valdur A. SaksEmail author
Article

Abstract

The role of ubiquitous mitochondrial creatine kinase (uMtCK) reaction in regulation of mitochondrial respiration was studied in purified preparations of rat brain synaptosomes and mitochondria. In permeabilized synaptosomes, apparent Km for exogenous ADP, Km (ADP), in regulation of respiration in situ was rather high (110 ± 11 μM) in comparison with isolated brain mitochondria (9 ± 1 μM). This apparent Km for ADP observed in isolated mitochondria in vitro dramatically increased to 169 ± 52 μM after their incubation with 1 μM of dimeric tubulin showing that in rat brain, particularly in synaptosomes, mitochondrial outer membrane permeability for ADP, and ATP may be restricted by tubulin binding to voltage dependent anion channel (VDAC). On the other hand, in synaptosomes apparent Km (ADP) decreased to 25 ± 1 μM in the presence of 20 mM creatine. To fully understand this effect of creatine on kinetics of respiration regulation, complete kinetic analysis of uMtCK reaction in isolated brain mitochondria was carried out. This showed that oxidative phosphorylation specifically altered only the dissociation constants for MgATP, by decreasing that from ternary complex MtCK.Cr.MgATP (K a) from 0.13 ± 0.02 to 0.018 ± 0.007 mM and that from binary complex MtCK.MgATP (K ia) from 1.1 ± 0.29 mM to 0.17 ± 0.07 mM. Apparent decrease of dissociation constants for MgATP reflects effective cycling of ATP and ADP between uMtCK and adenine nucleotide translocase (ANT). These results emphasize important role and various pathophysiological implications of the phosphocreatine–creatine kinase system in energy transfer in brain cells, including synaptosomes.

Keywords

Brain Creatine kinase Functional coupling Mitochondria Synaptosomes Tubulin 

Abbreviations

CK

Creatine kinase

uMtCK

Ubiquitous mitochondrial creatine kinase

sMtCK

Sarcomeric mitochondrial creatine kinase

Cr

Creatine

PCr

Phosphocreatine

ANT

Adenine nucleotide translocase

VDAC

Voltage dependent anion channel

DTT

Dithiothreitol

SDS

Sodium dodecyl sulfate

PEP

Phosphoenol pyruvate

PK

Pyruvate kinase

Notes

Acknowledgments

This work was supported by INSERM, France; Agence National de la Recherche (project n° BLAN07-2_188128), France, to C.M. and V.S.; grants of Estonian Science Foundation (N° 6142 and 7117 to V.S.).

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Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Claire Monge
    • 1
  • Nathalie Beraud
    • 1
  • Andrey V. Kuznetsov
    • 2
  • Tatiana Rostovtseva
    • 3
  • Dan Sackett
    • 4
  • Uwe Schlattner
    • 1
  • Marko Vendelin
    • 5
  • Valdur A. Saks
    • 1
    • 6
    • 7
    Email author
  1. 1.Laboratory of Fundamental and Applied BioenergeticsJoseph Fourier UniversityGrenobleFrance
  2. 2.Department of Transplant SurgeryD. Swarovski Research LaboratoryInnsbruckAustria
  3. 3.Laboratory of Physical and Structural BiologyNICHD, NIHBethesdaUSA
  4. 4.Laboratory of Integrative and Medical BiophysicsNICHD, NIHBethesdaUSA
  5. 5.Laboratory of Systems Biology, Institute of Cybernetics at TallinnUniversity of TechnologyTallinnEstonia
  6. 6.Laboratory of BioenergeticsNational Institute of Chemical Physics and BiophysicsTallinnEstonia
  7. 7.Grenoble Cedex 9France

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