Document Detail

Analyzing the functional properties of the creatine kinase system with multiscale 'sloppy' modeling.
MedLine Citation:
PMID:  21912519     Owner:  NLM     Status:  MEDLINE    
In this study the function of the two isoforms of creatine kinase (CK; EC 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.
Hannes Hettling; Johannes H G M van Beek
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-08-11
Journal Detail:
Title:  PLoS computational biology     Volume:  7     ISSN:  1553-7358     ISO Abbreviation:  PLoS Comput. Biol.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-09-13     Completed Date:  2011-12-20     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  101238922     Medline TA:  PLoS Comput Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e1002130     Citation Subset:  IM    
Centre for Integrative Bioinformatics VU, VU University Amsterdam, Amsterdam, The Netherlands.
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MeSH Terms
Adenosine Triphosphate / metabolism
Computational Biology / methods*
Creatine Kinase / metabolism*
Cytosol / metabolism
Energy Metabolism
Mitochondria / metabolism
Mitochondrial Membranes / metabolism
Models, Biological*
Monte Carlo Method
Myocardial Contraction / physiology
Myocardium / enzymology,  metabolism*
Phosphocreatine / metabolism
Reg. No./Substance:
0/Isoenzymes; 56-65-5/Adenosine Triphosphate; 67-07-2/Phosphocreatine; EC Kinase

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