An Integrated Model of Cardiac Mitochondrial Energy Metabolism and Calcium Dynamics

Abstract

We present an integrated thermokinetic model describing control of cardiac mitochondrial bioenergetics. The model describes the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and mitochondrial Ca(2+) handling. The kinetic component of the model includes effectors of the TCA cycle enzymes regulating production of NADH and FADH(2), which in turn are used by the electron transport chain to establish a proton motive force (Delta mu(H)), driving the F(1)F(0)-ATPase. In addition, mitochondrial matrix Ca(2+), determined by Ca(2+) uniporter and Na(+)/Ca(2+) 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 Ca(2+), 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 Ca(2+). The model is able to reproduce, qualitatively and semiquantitatively, experimental data concerning mitochondrial bioenergetics, Ca(2+) dynamics, and respiratory control. Significant increases in oxygen consumption (V(O(2))), proton efflux, NADH, and ATP synthesis, in response to an increase in cytoplasmic Ca(2+), are obtained when the Ca(2+)-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 Ca(2+) plays an important role in matching energy supply with demand in cardiac myocytes.

Mitochondrial‐Mediated Oxidative Ca 2+ /Calmodulin‐Dependent Kinase II Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An In Silico Study

“…As previously reported,5, 46, 47, 52, 56 increasing shunt , the fraction of the electrons of the respiratory chain towards the generation of ${\mathrm{O}}_{2^{·}}^{-}$ from 0.02 to 0.10 triggered sustained mitochondrial oscillations and cyclic ROS production (Figure S2A). The results indicate that addition of new model components (eg, mdROS‐mediated oxidative CaMKII activation and CaMKII‐dependent Na + channels phosphorylation) did not alter the dynamics of the existing model subsystems.…”

“…One unique characteristic of our ECME‐RIRR model is its capability to simulate sustained mitochondrial oscillations50, 56 (Figure S2A), allowing examination of the dynamics of AP upon mitochondrial repolarization 5, 52. As shown in Figure 5A, after ΔΨ m repolarization, AP EADs surprisingly remained on the first several (eg, 7 in this simulation) beats, even though mdROS had reduced to basal levels (Figure S2A).…”

Excitation-contraction coupling and mitochondrial energetics

“…The electrons that travel down the respiratory chain are eventually transferred to O 2 , forming H 2 O. O 2 consumption is respiration. At complex V of the respiratory chain (the F 1 /F 0 -ATPase), Δµ H provides the free energy for the generation of ATP from ADP (oxidative phosphorylation) [45,187]. …”

“…At complex V of the respiratory chain (the F 1 /F 0 -ATPase), Δµ H provides the free energy for the generation of ATP from ADP (oxidative phosphorylation) [45,187].…”

“…During CICR, bulk cytosolic Ca 2+ can be completely buffered with no effect of local EC coupling, as demonstrated in studies of "Ca 2+ spikes" [173,183]. Similarly, cytoplasmic high energy phosphate buffer systems (e.g., creatine kinase (CK) isoenzymes and the rapidly diffusable phosphocreatine, PCr) are present that can limit changes in bulk ATP while shuttling ADP to the mitochondrial adenine nucleotide transporter (ANT), effectively transferring the energetic signal from the site of ATP hydrolysis to the mitochondrion (reviewed in [164] [25,26,45,46,101,117,164] (see also further below in Bioenergetic consequences of mitochondrial Ca 2+ uptake). …”