Retarded diffusion of ADP in cardiomyocytes: possible role of mitochondrial outer membrane and creatine kinase in cellular regulation of oxidative phosphorylation

Saks, Valdur; Vasilyeva, Е. V.; Belikova, Yu. O.; Kuznetsov, Andrey V.; Lyapina, Svetlana; Petrova, L.; Perov, N. A.

doi:10.1016/0005-2728(93)90166-d

Cited by 121 publications

(93 citation statements)

References 44 publications

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“…They were one order of magnitude higher than those for ATP and ADP which are supposed to be limited in diffusion [11] and especially in mitochondrial membrane permeability [4]. In the following simulations the sensitivity of the model to the variations in the exchange rate constants was investigated.…”

Section: Variations In Diffusion Constantsmentioning

confidence: 99%

“…The values of the constants were chosen on the basis of the literature [2][3][4][19][20][21][22][23][24][25][26]. An interpretation of some of the rate constants is the following: k_Jk+5 =Km(ATP) for E2; k_7/k+7.~Ks(ADP) for E3; k_ 11/k+ 11 = Ks(ADP)Km(CrP) and k_ 12//k+ 12 = Ks(ATP)Km(Cr) for E 4.…”

Section: The Features Of the Cytoplasmic Enzymesmentioning

confidence: 99%

“…The ratio Xll/X12 varied from mode 1 to mode 5 to bring the steady state Pi concentration to ---2 mM which is known for the resting muscle [3,4,6,7]. The steady state concentrations of cytoplasmic metabolites at 'rest' were obtained after several iterations, going from initial X~ ..... X18 values, and are presented in Table 2.…”

Section: 'Resting System': Steady-state Concentrations Of Metabolitesmentioning

confidence: 99%

“…In the following simulations the sensitivity of the model to the variations in the exchange rate constants was investigated. The ADP constants were taken as minimal as this metabolite is believed to be the most diffusion restricted species in the ADP-ATP and Cr-CrP shuttles [3,4]. The constants for the other metabolites were assigned equal or 10 times higher than those for ADP, keeping the ratio kin//kout = 0.01 constant.…”

Section: Variations In Diffusion Constantsmentioning

confidence: 99%

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Creatine-creatine phosphate shuttle modeled as two-compartment system at different levels of creatine kinase activity

Fedosov

1994

Biochimica et Biophysica Acta (BBA) - Protein Structure and Mol

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In order to characterize ADP-ATP and creatine-creatine phosphate (Cr-CrP) shuttles a minimal mathematical model with two compartments and cyclic turnover of matter was designed. The 'mitochondrial' compartment contained 'ATP-synthase' and 'mitochondrial ereatine kinase' (mitCK). The 'cytoplasmic' compartment consisted of 'ATPase', 'cytoplasmic creatine kinase' (cytCK) and an 'ADP-binding structure'. The exchange of metabolites between these compartments was limited. Different levels of cytCK and mitCK expression as welt as different exchange rate constants between the compartments were assigned to obtain several different modes. Every steady state obtained in the presence of low ATPase activity ('resting' conditions) was then disturbed by a steep activation of ATPase ('muscle performance') and afterwards the transition to a new steady state was followed in time. The ATP-buffering capacity of the system initially acquired by cytCK expression significantly increased after additional mitCK supplement. Nevertheless, even the complete Cr-CrP shuttle failed to maintain a high [ATP]/[ADP] ratio during long term 'muscle performance' due to the rate limiting CK-transphosphorylation in the mitochondria. The facilitated diffusion of Cr and CrP was not critical, and the model worked with the same efficiency even at equal permeabilities for nucleotides and guanidines. Under 'resting conditions' the main flux of matter went through the Cr-CrP shuttle, resulting in 'pumping' of CrP. This ensured a 40 s delay in the [ATP] decrease at 'work'. The partial systems without mitCK were not as effective, and this delay was 0-10 s. However, the ADP-ATP shuttle was of more importance at the steady state achieved under ' working' conditions.

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Section: Variations In Diffusion Constantsmentioning

confidence: 99%

Section: The Features Of the Cytoplasmic Enzymesmentioning

confidence: 99%

Section: 'Resting System': Steady-state Concentrations Of Metabolitesmentioning

confidence: 99%

Section: Variations In Diffusion Constantsmentioning

confidence: 99%

See 2 more Smart Citations

Creatine-creatine phosphate shuttle modeled as two-compartment system at different levels of creatine kinase activity

Fedosov

1994

Biochimica et Biophysica Acta (BBA) - Protein Structure and Mol

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“…Inner and outer mitochondrial membranes are in close contact at certain sites. In the context of channelling of high-Gibbs-energy phosphates the issue has been raised of the relative location of adenine nucleotide translocase, creatine kinase, adenylate kinase, hexokinase, contact site and porin [28][29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

Control theory of metabolic channelling

1995

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Various factors appear to control muscle energetics, often in conjunction. This calls for a quantitative approach of the type provided by Metabolic Control Analysis for intermediary metabolism and mitochondrial oxidative phosphorylation. To the extent that direct transfer of high energy phosphates and spatial organization plays a role in muscle energetics however, the standard Metabolic Control Theory does not apply, neither do its theorems regarding control. This paper develops the Control Theory that does apply to the muscle system. It shows that direct transfer of high energy phosphates bestows a system with enhanced control: the sum of the control exerted by the participating enzymes on the flux of free energy from the mitochondrial matrix to the actinomyosin may well exceed the 100% mandatory for ideal metabolic pathways. It is also shown how sequestration of high energy phosphates may allow for negative control on pathway flux. The new control theory gives methods functionally to diagnose the extent to which channelling and metabolite sequestration occur. (Mol Cell Biochem 143: 151-168, 1995)

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Integrated and Organized Cellular Energetic Systems: Theories of Cell Energetics, Compartmentation, and Metabolic Channeling

Saks

Monge

Anmann

et al. 2007

Molecular System Bioenergetics

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Bioenergetics as a part of biophysical chemistry and biophysics is a quantitative science that is based on several fundamental theories. The definition of energy itself is given by the first law of thermodynamics, and application of the second law of thermodynamics shows that living cells can function as open systems only where the internal order (low entropy state) is maintained due to increasing the entropy in the surrounding medium (Schrödinger's principle of negentropy). For this, the exchange of mass is needed, which gives rise to metabolism as the sum of catabolism and anabolism, and the free energy changes during catabolic reactions supply energy for all cellular work -osmotic, mechanical, and biochemical. The free energy changes during metabolic reactions obey the rules of chemical thermodynamics, which deals with Gibbs free energy of chemical reactions and with electrochemical potentials. For application of these theories to the integrated systems in vivo, complex cellular organization should be accounted for: macromolecular crowding; metabolic channeling and functional coupling mechanisms due to close and tight protein-protein interactions; compartmentation of the enzymes due to their attachment to the subcellular membranes or connection to the cytoskeleton; and both macro-and microcompartmentation of substrates and metabolites in the cells. Because of this, almost all processes important for cell life are localized within small areas of the cell, and for their integration effective systems of communication, including compartmentalized energy transfer systems, are required. These are represented in muscle cells by the phosphotransfer networks, mostly by the creatine kinase and adenylate kinase systems, whose alterations under ischemic conditions contribute significantly to acute ischemic contractile failure of the heart. 59 Molecular System Bioenergetics: Energy for Life. Edited by Valdur Saks

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Retarded diffusion of ADP in cardiomyocytes: possible role of mitochondrial outer membrane and creatine kinase in cellular regulation of oxidative phosphorylation

Cited by 121 publications

References 44 publications

Creatine-creatine phosphate shuttle modeled as two-compartment system at different levels of creatine kinase activity

Creatine-creatine phosphate shuttle modeled as two-compartment system at different levels of creatine kinase activity

Control theory of metabolic channelling

Integrated and Organized Cellular Energetic Systems: Theories of Cell Energetics, Compartmentation, and Metabolic Channeling

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