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5.8 New Modeling Developments Along the
Experimental-Computational Synergy
The latest version of the isolated mitochondrion model—the mitochondrial
energetic-redox (ME-R) model—includes all four main redox couples NADH/
NAD + , NADPH/NADP + , GSH/GSSG, and Trx(SH) 2 /TrxSS together with a com-
plete array of antioxidant defenses. All four variables are considered as present in
two compartments: matrix and extra-mitochondrial; the latter compartment com-
prising intermembrane space and cytoplasm (Kembro et al. 2013 ). Also taken into
account are the NADP + -dependent isocitrate dehydrogenase (IDH2) in the TCA
cycle, and transhydrogenase (THD), two of the three main NADPH sources in
mitochondria. The Trx system involves thioredoxin reductase and peroxiredoxin
whilst the glutaredoxin system accounts for the recovery of glutathionylated
proteins (using GSH as cofactor), superoxide dismutases (SOD) (matrix-located
MnSOD and extra-mitochondrial Cu,ZnSOD), and catalase activity also in the
extra-mitochondrial compartment.
The model by Kembro et al. ( 2013 ) has been formulated on the basis of
our mitochondrial energetics version that included pH regulation, ion dynamics
(H + ,Ca 2+ ,Na + , Pi), respiratory fluxes from complex I and II, tricarboxylic acid
cycle (TCA cycle) dynamics, adenine nucleotide exchange (ANT), and ATP
synthesis (Wei et al. 2011 ).
The qualitative dynamic behavior exhibited by the new ME-R model reveals
that, as in former versions (Cortassa et al. 2004 ; Zhou et al. 2009 ), the underlying
oscillatory mechanism involves ROS imbalance determined by the interplay
between ROS production and scavenging as the main trigger of oscillations. This
happens irrespective of the bi-compartmental nature of the ME-R model, account-
ing for ROS scavenging in both the matrix and extra-mitochondrial space.
5.9 Conclusions
Experimental-computational synergy involves the reciprocal potentiation of the
loop involving experimental work and mathematical modeling that operates itera-
tively via the multiple simulation-validation and prediction-experimentation
Fig. 5.14 (continued) electrocardiogram (ECG, blue). (b) LV pressure and ECG in a heart during
diamide treatment showing the transition to ventricular fibrillation (VF, blue ) with concomitant
loss of pump function ( red ). (c) LV pressure and ECG in a heart during diamide treatment plus
64
m ( top ) and GSH ( bottom ) in intact guinea
pig hearts using two-photon microscopy after exposure to diamide (D) and diamide + 4 0
chlorodiazepam, 4 0 -ClDzp (e). The inset Di shows in detail the propagation of
μ
M 4'-ClDzp. (d, e) Simultaneous imaging of
ΔΨ
m depolarization
in the syncytium at the cardiomyocyte level. Reproduced from Brown, Aon, Frasier, Sloan,
Maloney, Anderson, O'Rourke (2010) J Mol Cell Cardiol 48, 673-679
ΔΨ
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