Diffusion of inorganic phosphate across the mitochondrial outer membrane
Maximum velocity Mi-CK (PCr production) without any inhibition by IAA of IA
fraction of time in the cardiac cycle where diastole takes place
Factor of inhibition of creatine kinase reaction when the heart is exposed to iodoacetic acid (IAA)
Permeability surface product for the permeability of the outer mitochondrial membrane to inorganic phosphate
Maximum velocity MM-CK (ATP production) without inhibition by IA or IAA
This model is from the article: Analyzing the functional properties of the creatine kinase system with multiscale 'sloppy' modeling. Hettling H, van Beek JH PLoS Comput Biol. 2011 Aug;7(8):e1002130. PMEDID , Abstract: 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. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2012 The BioModels.net Team. For more information see the terms of use . To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
Diffusion of creatine across the mitochondrial outer membrane
fraction of time in the cardiac cycle where systole takes place and where the energy demand is still increasing (before the energy consumption peak)
Time constant of ATP synthesis time course in response to a step in ATP demand
Factor of inhibition of creatine kinase reaction when the heart is exposed to iodoacetamide (IA)
Permeability surface product for the permeability of the outer mitochondrial membrane to creatine
Internal parameter for tmito calculation. Value is zero in base condition, otherwise one
Average ATP hydrolysis at base condition
Permeability surface product for the permeability of the outer mitochondrial membrane to phosphocreatine
Permeability surface product for the permeability of the outer mitochondrial membrane to ATP and ADP
Last time in simulation where the 'pulsatile' event took place
Denominator for ATP synthsis rearction term, see eq. A25 in van Beek, Am J Physiol Cell Physiol. 2007 Sep;293(3):C815-29
Equilibrium constant for Mi-CK and MM-CK
Diffusion of ATP across the mitochondrial outer membrane
Fraction of high-energy phosphate transported across the mitochondrial outer membrane via phosphocreatine
Time point in simulation, where the heart rate is increased (base condition to test condition)
Diffusion of phosphocreatine across the mitochondrial outer membrane
Average rate of ATP hydrolysis at test condition
Flux of mitochondrial creatine kinase reaction
1 if simulation with pulsatile ATP hydrolysis function is desired, otherwise 0
heart rate at base condition (before heart rate gets altered)
fraction of time in the cardiac cycle where systole takes place and where the energy demand is decreasing (after the energy consumption peak)
Flux of cytosolic creatine kinase reaction
Amplitude of ATP hydrolysis time course at base condition (lower heart rate)
Amplitude of ATP hydrolysis time course at test condition (elevated heart rate)
Diffusion of ADP across the mitochondrial outer membrane
Apparent Km mitochondria for inorganic phosphate