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

Abstract

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.

Predicting the influence of long-range molecular interactions on macroscopic-scale diffusion by homogenization of the Smoluchowski equation

“…Furthermore, the generality of the Smoluchowski equation for potentials of mean force arising from a variety of molecular interactions suggests that its homogenization may bridge a variety of diffusioncoupled phenomena across spatial scales, especially where densely packed proteins and macromolecular structures are concerned. Such examples could include metabolic fluxes within the sarcomere 46,47 and "compartmentalized" cyclic adenosine monophosphate (cAMP) signaling via localized Akinase anchor proteins (AKAP) complexes. 48 We, furthermore, see the prospect of using the HSE to describe molecular phenomena well-represented by low-dimensional diffusional processes subject to a potential of mean force, such as the sliding of proteins along DNA.…”

Molecular System Bioenergics of the Heart: Experimental Studies of Metabolic Compartmentation and Energy Fluxes versus Computer Modeling

“…High t mito values in System A-type simulations permitted van Beek to lower MOM permeability to obtain t mito about 4 s [103]. This result can be reproduced by our model on decreasing the MOM permeability restriction coefficient from 0.007 to 0.1 (Third line in Table 1).…”

“…[75]. Basing both on model simulation and experimental data, we can conclude that an assumption of van Beek [103] on nullifying the MtCK to ANT coupling at millimolar ATP levels cannot be regarded as justified, since they have not accounted for the differences in mitochondrial behavior in vitro and in vivo .…”

Kir6.2 limits Ca2+ overload and mitochondrial oscillations of ventricular myocytes in response to metabolic stress

“…It is possible that a decrease in K ATP channel density might disrupt this phosphotransfer bridge (6,45). Indeed, knockout of creatine kinase from cardiac myocytes causes uncoupling of metabolic signals such that K ATP channels open significantly earlier in response to metabolic stress (41).…”