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
In order to be able to rapidly adapt to environmental changes, biological systems require dynamic control systems which function near the edge of instability. Dynamic control can be in the form of oscillations, such as cytosolic calcium concentration oscillations(eg Sneyd et al., Modelling the Control of Calcium Oscillations by Membrane Fluxes, 2004), electrical pacemaker cells (eg Lovell et al., A Gradient Model Of Cardiac Pacemaker Myocytes, 2004), and secretion of insulin from pancreatic islets (eg Keener, A Model of Diffusion Induced Oscillatory Insulin Secretion in Pancreatic Beta Cells, 2001)
Oscillations in energy metabolism also occur for example in mitochondria, there are oscillations in the transmembrane ionic currents. Experimental data have shown that oscillation of the mitochondrial energy state occur as a consequence of the interactions between mitochondrial reactive oxygen species (ROS) production and the ROS scavenging systems of the cell. In the current study, Cortassa et al. use this experimental data as the basis for their mathematical model, which incorporates mitochondrial ROS synthesis, ROS scavenging, and ion channels within the mitochondrial membrane (see Figure 1 below). This mathematical model of a mitochondrial oscillator is embedded within a previously published model of cardiac mitochondrial energetics (see Cortassa et al. Modelling Mitochondrial Energy Metabolism, 2003, and also see Figure 2 below for more details)
Model simulations have generated data which match experimental results. Furthermore, the model simulations also demonstrate that the period of the mitochondrial oscillator can be modulated over a wide range of timescales, from milliseconds to hours, by altering a single parameter, the rate of ROS scavenging by the enzyme superoxide dismutase.
The complete original paper reference is cited below:
A Mitochondrial Oscillator Dependent on Reactive Oxygen Species, Sonia Cortassa, Miguel A. Aon, Raimond L. Winslow, and Brian O'Rourke, 2004, Biophysical Journal, 87, 2060-2073.PubMed ID: 15345581
reaction diagram
Figure 1. A schematic diagram of mitochondrial energetics coupled to ROS production, transport, and scavenging. These processes are described by the equations in Cortassa et al.'s 2004 mathematical model
reaction diagram
Figure 2. 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
NADPH
reduced nicotinamide adenine dinucleotide phosphate
O2_m
mitochondrial superoxide radical
O2_i
cytoplasmic superoxide radical
H2O2
hydrogen peroxide
GSH
glutathione
GSSG
glutathione disulphide
CIT
citric acid
V_SOD
superoxide dismutase
V_CAT
Catalase
V_GPX
Glutathione peroxidase
V_GR
Glutathione reductase
V_IMAC
mitochondrial inner membrane anion channel conductance
VTr_ROS
transport of reactive oxygen species across the inner mitochondrial membrane
Catherine
Lloyd
May
2004-09-00 00:00
15345581
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.
Miguel
Aon
A
Catherine
Lloyd
May
The University of Auckland
Auckland Bioengineering Institute
2009-04-30T10:21:14+12:00
Sonia
Cortassa
Biophysical Journal
Brian
O'Rourke
c.lloyd@auckland.ac.nz
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.
Also added a component for NADPH as it is required in the equation for V_CAT (we are awaiting confirmation from the model author for the actual concentration of this variable). "fr" in V_CAT was changed from dimensionless to mM-1 in order to balance the units.
Catherine Lloyd
A mitochondrial oscillator dependent on reactive oxygen species
87
2060
2073
Raimond
Winslow
L
2004-09-28T00:00:00+00:00