Steady-state kinetics of the overall oxidative phosphorylation reaction in heart mitochondria

Stoner, Clinton D.; Sirak, Howard D.

doi:10.1007/bf00743199

Cited by 24 publications

(11 citation statements)

References 44 publications

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“…Both parameters occur in the model equation determining the rate of oxidative phosphorylation, which may explain the inverse variation. There exist in vitro measurements of K pi that are lower than the initial value used in this analysis [18]: Stoner & Sirak for instance measured K pi to be 360 µM [23] which is close to our optimized value. Likewise, reported values for K adp vary between 20 and 30 µM [24], [25], corroborating the values obtained by the fit.…”

Section: Resultssupporting

confidence: 65%

Analyzing the Functional Properties of the Creatine Kinase System with Multiscale ‘Sloppy’ Modeling

Hettling

Beek

2011

PLoS Comput Biol

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In this study the function of the two isoforms of creatine kinase (CK; EC 2.7.3.2) in myocardium is investigated. The ‘phosphocreatine shuttle’ hypothesis states that mitochondrial and cytosolic CK plays a pivotal role in the transport of high-energy phosphate (HEP) groups from mitochondria to myofibrils in contracting muscle. Temporal buffering of changes in ATP and ADP is another potential role of CK. With a mathematical model, we analyzed energy transport and damping of high peaks of ATP hydrolysis during the cardiac cycle. The analysis was based on multiscale data measured at the level of isolated enzymes, isolated mitochondria and on dynamic response times of oxidative phosphorylation measured at the whole heart level. Using ‘sloppy modeling’ ensemble simulations, we derived confidence intervals for predictions of the contributions by phosphocreatine (PCr) and ATP to the transfer of HEP from mitochondria to sites of ATP hydrolysis. Our calculations indicate that only 15±8% (mean±SD) of transcytosolic energy transport is carried by PCr, contradicting the PCr shuttle hypothesis. We also predicted temporal buffering capabilities of the CK isoforms protecting against high peaks of ATP hydrolysis (3750 µM*s−1) in myofibrils. CK inhibition by 98% in silico leads to an increase in amplitude of mitochondrial ATP synthesis pulsation from 215±23 to 566±31 µM*s−1, while amplitudes of oscillations in cytosolic ADP concentration double from 77±11 to 146±1 µM. Our findings indicate that CK acts as a large bandwidth high-capacity temporal energy buffer maintaining cellular ATP homeostasis and reducing oscillations in mitochondrial metabolism. However, the contribution of CK to the transport of high-energy phosphate groups appears limited. Mitochondrial CK activity lowers cytosolic inorganic phosphate levels while cytosolic CK has the opposite effect.

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Section: Resultssupporting

confidence: 65%

Analyzing the Functional Properties of the Creatine Kinase System with Multiscale ‘Sloppy’ Modeling

Hettling

Beek

2011

PLoS Comput Biol

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“…This equation lumps the complex processes involving the mitochondrial adenine nucleotide translocator, mitochondrial matrix, inner membrane proton pumps, and electrical potential in a simple overall equation which has been tested extensively on isolated mitochondria (16,36) and is used often for modeling (19,25). ATP production is given by a simple Michaelis-Menten-type equation as a function of the ADP and P i concentrations (see APPENDIX A).…”

Section: Methodsmentioning

confidence: 99%

“…The crucial point is that this equation has been experimentally validated (16,36). The crucial point is that this equation has been experimentally validated (16,36).…”

Section: Equations For the Adenine Nucleotide-creatine-phosphate Modulementioning

confidence: 99%

Adenine nucleotide-creatine-phosphate module in myocardial metabolic system explains fast phase of dynamic regulation of oxidative phosphorylation

Beek¹

2007

American Journal of Physiology-Cell Physiology

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Computational models of a large metabolic system can be assembled from modules that represent a biological function emerging from interaction of a small subset of molecules. A "skeleton model" is tested here for a module that regulates the first phase of dynamic adaptation of oxidative phosphorylation (OxPhos) to demand in heart muscle cells. The model contains only diffusion, mitochondrial outer membrane (MOM) permeation, and two isoforms of creatine kinase (CK), in cytosol and mitochondrial intermembrane space (IMS), respectively. The communication with two neighboring modules occurs via stimulation of mitochondrial ATP production by ADP and P(i) from the IMS and via time-varying cytosolic ATP hydrolysis during contraction. Assuming normal cytosolic diffusion and high MOM permeability for ADP, the response time of OxPhos (t(mito); generalized time constant) to steps in cardiac pacing rate is predicted to be 2.4 s. In contrast, with low MOM permeability, t(mito) is predicted to be 15 s. An optimized MOM permeability of 21 mum/s gives t(mito) = 3.7 s, in agreement with experiments on rabbit heart with blocked glycolytic ATP synthesis. The model correctly predicts a lower t(mito) if CK activity is reduced by 98%. Among others, the following predictions result from the model analysis: 1) CK activity buffers large ADP oscillations; 2) ATP production is pulsatile in beating heart, although it adapts slowly to demand with "time constant" approximately 14 heartbeats; 3) if the muscle isoform of CK is overexpressed, OxPhos reacts slower to changing workload; and 4) if mitochondrial CK is overexpressed, OxPhos reacts faster.

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“…In most experimental studies the VO 2 -[ADP] relationship in isolated mitochondria is hyperbolic (first order al low [ADP]) (see e.g. [31][32][33]) .…”

Section: Comparison Of Different Mechanisms Of Regulation Of Oxidativmentioning

confidence: 99%

Regulation of oxidative phosphorylation through parallel activation

Korzeniewski

2007

Biophysical Chemistry

119

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When the mechanical work intensity in muscle increases, the elevated ATP consumption rate must be matched by the rate of ATP production by oxidative phosphorylation in order to avoid a quick exhaustion of ATP. The traditional mechanism of the regulation of oxidative phosphorylation, namely the negative feedback involving [ADP] and [P i ] as regulatory signals, is not sufficient to account for various kinetic properties of the system in intact skeletal muscle and heart in vivo. Theoretical studies conducted using a dynamic computer model of oxidative phosphorylation developed previously strongly suggest the so-called each-step-activation (or parallel-activation) mechanism, due to which all oxidative phosphorylation complexes are directly activated by some cytosolic factor/mechanism related to muscle contraction in parallel with the activation of ATP usage and substrate dehydrogenation by calcium ions. The present polemic article reviews and discusses the growing evidence supporting this mechanism and compares it with alternative mechanisms proposed in the literature. It is concluded that only the each-step-activation mechanism is able to explain the rich set of various experimental results used as a reference for estimating the validity and applicability of particular mechanisms.

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Steady-state kinetics of the overall oxidative phosphorylation reaction in heart mitochondria

Cited by 24 publications

References 44 publications

Analyzing the Functional Properties of the Creatine Kinase System with Multiscale ‘Sloppy’ Modeling

Analyzing the Functional Properties of the Creatine Kinase System with Multiscale ‘Sloppy’ Modeling

Adenine nucleotide-creatine-phosphate module in myocardial metabolic system explains fast phase of dynamic regulation of oxidative phosphorylation

Regulation of oxidative phosphorylation through parallel activation

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