Modelling Mitochondrial Energy Metabolism
Catherine
Lloyd
Bioengineering Institute, University of Auckland
Model Status
This CellML model has been checked in both OpenCell and COR and the units are consistent. Unfortunately the model will not integrate at the moment. We are working with the model author to complete the curation of this model.
Model Structure
The high metabolic rate of cardiac tissue necessitates close agreement between the rates of energy production and consumption. About 2 percent of cellular ATP is consumed per heartbeat, and under normal conditions, almost all of this energy is provided by mitochondrial oxidative phosphorylation. Although the chemiosmotic theory of energy transduction was developed by Michell in 1961, remarkably little has since been elucidated about the mechanisms underlying the control of mitochondrial metabolism.
The thermokinetic model describes the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and mitochondrial Ca2+ dynamics (see below). The kinetic portion of the model includes effectors of the TCA cycle enzymes regulating production of NADH and FADH2. In turn, these are used by the electron transport chain to establish a proton motive force driving the F1F0-ATPase. In addition, mitochondrial matrix Ca2+, determined by Ca2+ uniporter and Ca2+/Na+ exchanger activities, controls the activity of the TCA cycle enzymes isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase. Model simulations are used to predict the response of mitochondria to changes in substrate delivery, metabolic inhibition, the rate of ATP/ADP exchange, and Ca2+ concentration. Model simulations are able to reproduce experimental data, which was taken as supporting evidence for the validity of the model. The steady-state and time-dependent behaviour of the model supports the hypothesis that mitochondrial matrix Ca2+ plays an important role in matching energy supply with demand in cardiac myocytes.
Previously published models of mitochondrial energetics include the models of pancreatic beta-cell mitochondrial metabolism by Magnus and Keizer (see Mitochondrial Ca2+ Handling Model, 1997). An oxidative phosphorylation model has been developed by Korzeniewski (see The Oxidative Phosphorylation Pathway, 2001). However, these models, in common with other previously developed models of mitochondrial energetics, fail to include all the necessary variables. Together with the desire to improve understanding of mitochondrial metabolism, this has led Cortassa et al. to develop an integrated kinetic and thermodynamic model of cardiac mitochondrial energy metabolism. Their model has been described here in CellML (the raw CellML description of the Cortassa et al. model can be downloaded in various formats as described in ).
The complete original paper reference is cited below:
An Integrated Model of Cardiac Mitochondrial Energy Metabolism and Calcium Dynamics, Sonia Cortassa, Miguel A. Aon, Eduardo Marban, Raimond L. Winslow, and Brian O'Rourke, 2003,
Biophysical Journal
, 84, 2734-2755. (Full text (HTML) and PDF versions of the article are available on the Biophysical Journal website.) PubMed ID: 12668482
reaction diagram
A schematic diagram of the reactions used in the model of the glycogenolysis pathway in skeletal muscle.
ADP_m
mitochondrial adenosine diphosphate
NADH
nicotinamide adenine dinucleotide
ISOC
isocitrate
alpha_KG
alpha-ketoglutarate
SCoA
succinyl CoA
Suc
succinate
FUM
fumarate
MAL
malate
OAA
oxaloacetate
ASP
aspartate
Ca_m
mitochondrial calcium
Ca_i
cytosolic calcium
Na_i
cytosolic sodium
ATP_i
cytosolic adenosine triphosphate
ATP_m
mitochondrial adenosine triphosphate
ADP_i
cytosolic adenosine diphosphate
GLU
glutamate
Mg
magnesium
H
proton
Pi
inorganic phosphate
CoA
Coenzyme A
AcCoA
acetyl Coenzyme A
FAD
flavin adenine dinucleotide (oxidised)
FADH2
flavin adenine dinucleotide (reduced)
NAD
charged nicotinamide adenine dinucleotide
CIT
citric acid
calcium dynamics
metabolism
cardiac
electrophysiology
2003-05-13T00:00:00+00:00
Raimond
Winslow
L
Miguel
Aon
A
keyword
Catherine
Lloyd
May
The University of Auckland, Bioengineering Institute
An Integrated Model of Cardiac Mitrochondrial Energy Metabolism and Calcium Dynamics
84
2734
2755
This CellML model has been checked in both OpenCell and COR and the units are consistent. Unfortunately the model will not integrate at the moment. We are working with the model author to complete the curation of this model.
Eduardo
Marban
Added initial conditions for the metabolites. Added a concentration for GLU (glutamate) - this is temporary until the model author confirms the value they used in the original model. Added a value for "ni" in V_IDH (again this is temporary until the model author confirms the value they used in the original model). Kf_AAT is 2nd order not 1st order (in order to balance units). Similarly, Ke_SL and KF1 are mM not dimensionless in order to balance the units.
This is the CellML description of Cortassa et al.'s 2003 integrated model of cardiac mitochondrial energy metabolism and calcium dynamics.
Brian
O'Rourke
12668482
Sonia
Cortassa
Catherine Lloyd
Cortassa et al.'s 2003 integrated model of cardiac mitochondrial energy
metabolism and calcium dynamics.
cardiac myocyte
c.lloyd@auckland.ac.nz
Biophysical Journal
2003-04
Catherine
Lloyd
May
Catherine Lloyd
The University of Auckland
The Bioengineering Institute
2009-04-30T10:16:03+12:00