help button home button Biophys. J.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Appendix
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cortassa, S.
Right arrow Articles by O'Rourke, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cortassa, S.
Right arrow Articles by O'Rourke, B.
Biophysical Journal 84:2734-2755 (2003)
© 2003 The Biophysical Society

An Integrated Model of Cardiac Mitochondrial Energy Metabolism and Calcium Dynamics

Sonia Cortassa*, Miguel A. Aon*, Eduardo Marbán*,{dagger}, Raimond L. Winslow{dagger},* and Brian O'Rourke*

The Johns Hopkins University, * Institute of Molecular Cardiobiology and {dagger} The Center for Computational Medicine and Biology, Baltimore, Maryland

Correspondence: Address reprint requests to Brian O'Rourke, Ph.D., The Johns Hopkins University, Institute of Molecular Cardiobiology, 720 Rutland Ave., 844 Ross Bldg., Baltimore, MD 21205-2195. Tel.: 410-614-0034; Fax: 410-955-7953; e-mail: bor{at}jhmi.edu.

We present an integrated thermokinetic model describing control of cardiac mitochondrial bioenergetics. The model describes the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and mitochondrial Ca2+ handling. The kinetic component of the model includes effectors of the TCA cycle enzymes regulating production of NADH and FADH2, which in turn are used by the electron transport chain to establish a proton motive force ({Delta}µH), driving the F1F0-ATPase. In addition, mitochondrial matrix Ca2+, determined by Ca2+ uniporter and Na+/Ca2+ exchanger activities, regulates activity of the TCA cycle enzymes isocitrate dehydrogenase and {alpha}-ketoglutarate dehydrogenase. The model is described by twelve ordinary differential equations for the time rate of change of mitochondrial membrane potential ({Delta}{Psi}m), and matrix concentrations of Ca2+, NADH, ADP, and TCA cycle intermediates. The model is used to predict the response of mitochondria to changes in substrate delivery, metabolic inhibition, the rate of adenine nucleotide exchange, and Ca2+. The model is able to reproduce, qualitatively and semiquantitatively, experimental data concerning mitochondrial bioenergetics, Ca2+ dynamics, and respiratory control. Significant increases in oxygen consumption (VO2), proton efflux, NADH, and ATP synthesis, in response to an increase in cytoplasmic Ca2+, are obtained when the Ca2+-sensitive dehydrogenases are the main rate-controlling steps of respiratory flux. These responses diminished when control is shifted downstream (e.g., the respiratory chain or adenine nucleotide translocator). The time-dependent behavior of the model, under conditions simulating an increase in workload, closely reproduces experimentally observed mitochondrial NADH dynamics in heart trabeculae subjected to changes in pacing frequency. The steady-state and time-dependent behavior of the model support the hypothesis that mitochondrial matrix Ca2+ plays an important role in matching energy supply with demand in cardiac myocytes.




This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
J. Dzbek and B. Korzeniewski
Control Over the Contribution of the Mitochondrial Membrane Potential ({Delta}{Psi}) and Proton Gradient ({Delta}pH) to the Protonmotive Force ({Delta}p): IN SILICO STUDIES
J. Biol. Chem., November 28, 2008; 283(48): 33232 - 33239.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
R. K. Dash and D. A. Beard
Analysis of cardiac mitochondrial Na+-Ca2+ exchanger kinetics with a biophysical model of mitochondrial Ca2+ handing suggests a 3: 1 stoichiometry
J. Physiol., July 1, 2008; 586(13): 3267 - 3285.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
L. Zhou, M. E. Cabrera, H. Huang, C. L. Yuan, D. K. Monika, N. Sharma, F. Bian, and W. C. Stanley
Parallel activation of mitochondrial oxidative metabolism with increased cardiac energy expenditure is not dependent on fatty acid oxidation in pigs
J. Physiol., March 15, 2007; 579(3): 811 - 821.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
R. S. Balaban
Modeling mitochondrial function
Am J Physiol Cell Physiol, December 1, 2006; 291(6): C1107 - C1113.
[Abstract] [Full Text] [PDF]

Home page
 Biophys. JHome page
M. A. Aon, S. Cortassa, and B. O'Rourke
The Fundamental Organization of Cardiac Mitochondria as a Network of Coupled Oscillators
Biophys. J., December 1, 2006; 91(11): 4317 - 4327.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
C. Camello-Almaraz, P. J. Gomez-Pinilla, M. J. Pozo, and P. J. Camello
Mitochondrial reactive oxygen species and Ca2+ signaling
Am J Physiol Cell Physiol, November 1, 2006; 291(5): C1082 - C1088.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
L. Zhou, M. E. Cabrera, I. C. Okere, N. Sharma, and W. C. Stanley
Regulation of myocardial substrate metabolism during increased energy expenditure: insights from computational studies
Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1036 - H1046.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
B. Korzeniewski
Oxygen consumption and metabolite concentrations during transitions between different work intensities in heart
Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1466 - H1474.
[Abstract] [Full Text] [PDF]

Home page
 Biophys. JHome page
S. Cortassa, M. A. Aon, B. O'Rourke, R. Jacques, H.-J. Tseng, E. Marban, and R. L. Winslow
A Computational Model Integrating Electrophysiology, Contraction, and Mitochondrial Bioenergetics in the Ventricular Myocyte
Biophys. J., August 15, 2006; 91(4): 1564 - 1589.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
W.-K. Lee and F. Thevenod
A role for mitochondrial aquaporins in cellular life-and-death decisions?
Am J Physiol Cell Physiol, August 1, 2006; 291(2): C195 - C202.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
C. Maack, S. Cortassa, M. A. Aon, A. N. Ganesan, T. Liu, and B. O'Rourke
Elevated Cytosolic Na+ Decreases Mitochondrial Ca2+ Uptake During Excitation-Contraction Coupling and Impairs Energetic Adaptation in Cardiac Myocytes
Circ. Res., July 21, 2006; 99(2): 172 - 182.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
V. Saks, P. Dzeja, U. Schlattner, M. Vendelin, A. Terzic, and T. Wallimann
Cardiac system bioenergetics: metabolic basis of the Frank-Starling law
J. Physiol., March 1, 2006; 571(2): 253 - 273.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
L. Zhou, W. C. Stanley, G. M. Saidel, X. Yu, and M. E. Cabrera
Regulation of lactate production at the onset of ischaemia is independent of mitochondrial NADH/NAD+: insights from in silico studies
J. Physiol., December 15, 2005; 569(3): 925 - 937.
[Abstract] [Full Text] [PDF]

Home page
 PhysiologyHome page
B. O'Rourke, S. Cortassa, and M. A. Aon
Mitochondrial Ion Channels: Gatekeepers of Life and Death
Physiology, October 1, 2005; 20(5): 303 - 315.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
R. Kovacs, J. Kardos, U. Heinemann, and O. Kann
Mitochondrial Calcium Ion and Membrane Potential Transients Follow the Pattern of Epileptiform Discharges in Hippocampal Slice Cultures
J. Neurosci., April 27, 2005; 25(17): 4260 - 4269.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
R. L Winslow, S. Cortassa, and J. L Greenstein
Using models of the myocyte for functional interpretation of cardiac proteomic data
J. Physiol., February 15, 2005; 563(1): 73 - 81.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
R. L. Winslow and J. L. Greenstein
The Ongoing Journey to Understand Heart Function Through Integrative Modeling
Circ. Res., December 10, 2004; 95(12): 1135 - 1136.
[Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
H. I. Gursahani and S. Schaefer
Acidification reduces mitochondrial calcium uptake in rat cardiac mitochondria
Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2659 - H2665.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
T. D. Vo, H. J. Greenberg, and B. O. Palsson
Reconstruction and Functional Characterization of the Human Mitochondrial Metabolic Network Based on Proteomic and Biochemical Data
J. Biol. Chem., September 17, 2004; 279(38): 39532 - 39540.
[Abstract] [Full Text] [PDF]

Home page
 Biophys. JHome page
S. Cortassa, M. A. Aon, R. L. Winslow, and B. O'Rourke
A Mitochondrial Oscillator Dependent on Reactive Oxygen Species
Biophys. J., September 1, 2004; 87(3): 2060 - 2073.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
C. J. DOUGHERTY, L. A. KUBASIAK, D. P. FRAZIER, H. LI, W.-CHENG. XIONG, N. H. BISHOPRIC, and K. A. WEBSTER
Mitochondrial signals initiate the activation of c-Jun N-terminal kinase (JNK) by hypoxia-reoxygenation
FASEB J, July 1, 2004; 18(10): 1060 - 1070.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. A. Aon, S. Cortassa, and B. O'Rourke
Percolation and criticality in a mitochondrial network
PNAS, March 30, 2004; 101(13): 4447 - 4452.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. A. Aon, S. Cortassa, E. Marban, and B. O'Rourke
Synchronized Whole Cell Oscillations in Mitochondrial Metabolism Triggered by a Local Release of Reactive Oxygen Species in Cardiac Myocytes
J. Biol. Chem., November 7, 2003; 278(45): 44735 - 44744.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2003 by the Biophysical Society.