PMID- 17581855
OWN - NLM
STAT- MEDLINE
DCOM- 20071029
LR  - 20200930
IS  - 0363-6143 (Print)
IS  - 0363-6143 (Linking)
VI  - 293
IP  - 3
DP  - 2007 Sep
TI  - Adenine nucleotide-creatine-phosphate module in myocardial metabolic system 
      explains fast phase of dynamic regulation of oxidative phosphorylation.
PG  - C815-29
AB  - 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.
FAU - van Beek, Johannes H G M
AU  - van Beek JH
AD  - Dept. of Molecular Cell Physiology, FALW, Vrije Universiteit, De Boelelaan 1085, 
      1081 HV Amsterdam. hans.van.beek@falw.vu.nl
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070620
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (Phosphates)
RN  - 020IUV4N33 (Phosphocreatine)
RN  - 61D2G4IYVH (Adenosine Diphosphate)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.3.2 (Creatine Kinase, MM Form)
RN  - EC 2.7.3.2 (Creatine Kinase, Mitochondrial Form)
RN  - JAC85A2161 (Adenine)
RN  - MU72812GK0 (Creatine)
SB  - IM
MH  - Adenine/*metabolism
MH  - Adenosine Diphosphate/metabolism
MH  - Adenosine Triphosphate/biosynthesis/metabolism
MH  - Animals
MH  - Creatine/*metabolism
MH  - Creatine Kinase, MM Form/metabolism
MH  - Creatine Kinase, Mitochondrial Form/metabolism
MH  - Diffusion
MH  - Heart Rate/physiology
MH  - Hydrolysis
MH  - Mitochondria/metabolism
MH  - Models, Biological
MH  - Myocardial Contraction/*physiology
MH  - Myocytes, Cardiac/*metabolism
MH  - Nuclear Magnetic Resonance, Biomolecular
MH  - Oxidative Phosphorylation
MH  - Oxygen Consumption/physiology
MH  - Phosphates/*metabolism
MH  - Phosphocreatine/metabolism
MH  - Rabbits
EDAT- 2007/06/22 09:00
MHDA- 2007/10/30 09:00
CRDT- 2007/06/22 09:00
PHST- 2007/06/22 09:00 [pubmed]
PHST- 2007/10/30 09:00 [medline]
PHST- 2007/06/22 09:00 [entrez]
AID - 00355.2006 [pii]
AID - 10.1152/ajpcell.00355.2006 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2007 Sep;293(3):C815-29. doi: 
      10.1152/ajpcell.00355.2006. Epub 2007 Jun 20.