A Reaction-Diffusion Model of ROS-Induced ROS Release in a Mitochondrial Network

Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS Computational Biology (Impact Factor: 4.62). 01/2010; 6(1):e1000657. DOI: 10.1371/journal.pcbi.1000657
Source: PubMed


Loss of mitochondrial function is a fundamental determinant of cell injury and death. In heart cells under metabolic stress, we have previously described how the abrupt collapse or oscillation of the mitochondrial energy state is synchronized across the mitochondrial network by local interactions dependent upon reactive oxygen species (ROS). Here, we develop a mathematical model of ROS-induced ROS release (RIRR) based on reaction-diffusion (RD-RIRR) in one- and two-dimensional mitochondrial networks. The nodes of the RD-RIRR network are comprised of models of individual mitochondria that include a mechanism of ROS-dependent oscillation based on the interplay between ROS production, transport, and scavenging; and incorporating the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and Ca(2+) handling. Local mitochondrial interaction is mediated by superoxide (O2.-) diffusion and the O2.(-)-dependent activation of an inner membrane anion channel (IMAC). In a 2D network composed of 500 mitochondria, model simulations reveal DeltaPsi(m) depolarization waves similar to those observed when isolated guinea pig cardiomyocytes are subjected to a localized laser-flash or antioxidant depletion. The sensitivity of the propagation rate of the depolarization wave to O(2.-) diffusion, production, and scavenging in the reaction-diffusion model is similar to that observed experimentally. In addition, we present novel experimental evidence, obtained in permeabilized cardiomyocytes, confirming that DeltaPsi(m) depolarization is mediated specifically by O2.-). The present work demonstrates that the observed emergent macroscopic properties of the mitochondrial network can be reproduced in a reaction-diffusion model of RIRR. Moreover, the findings have uncovered a novel aspect of the synchronization mechanism, which is that clusters of mitochondria that are oscillating can entrain mitochondria that would otherwise display stable dynamics. The work identifies the fundamental mechanisms leading from the failure of individual organelles to the whole cell, thus it has important implications for understanding cell death during the progression of heart disease.

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    • "If a number of mitochondria in the network approach a threshold of redox stress, a state called mitochondrial criticality is reached, rendering the mitochondria hypersensitive to small perturbations. In this state, depolarization of only a few mitochondria can lead to a propagated wave of depolarization, complete collapse, or oscillation of ΔΨ m in the whole network of a cardiac myocyte [12] [13] [14]. Coupling between mitochondria occurs through the autocatalytic mechanism called ROSinduced ROS-release (RIRR) [15] [16] [17]. "
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    ABSTRACT: Regional depolarization of the mitochondrial network can alter cellular electrical excitability and increase the propensity for reentry, in part, through the opening of sarcolemmal KATP channels. Mitochondrial inner membrane potential (ΔΨm) instability or oscillation can be induced in myocytes by exposure to reactive oxygen species (ROS), laser excitation, or glutathione depletion, and is thought to be a major factor in arrhythmogenesis during ischemia–reperfusion. Nevertheless, the correlation between ΔΨm recovery kinetics and reperfusion-induced arrhythmias has been difficult to demonstrate experimentally. Here, we investigate the relationship between subcellular changes in ΔΨm, cellular glutathione redox potential, electrical excitability, and wave propagation during coverslip-induced ischemia–reperfusion (IR) in neonatal rat ventricular myocyte (NRVM) monolayers. Ischemia led to decreased action potential amplitude and duration followed by electrical inexcitability after ~ 15 min of ischemia. ΔΨm depolarization occurred in two phases during ischemia: in phase 1 (< 30 min ischemia), mitochondrial clusters within individual NRVMs depolarized, while phase 2 ΔΨm depolarization (30–60 min) was characterized by global functional collapse of the mitochondrial network across the whole ischemic region of the monolayer, typically involving a propagating metabolic wave. Oxidation of the glutathione (GSSG:GSH) redox potential occurred during ischemia, followed by recovery upon reperfusion (i.e., lifting the coverslip). ΔΨm recovered in the mitochondria of individual myocytes quite rapidly upon reperfusion (< 5 min), but was highly unstable, characterized by subcellular oscillations or flickering of clusters of mitochondria in NRVMs across the reperfused region. Electrical excitability also recovered in a heterogeneous manner, providing an arrhythmogenic substrate which led to formation of sustained reentry. Treatment with 4′-chlorodiazepam, a peripheral benzodiazepine receptor ligand, prevented ΔΨm oscillation, improved GSH recovery rate, and prevented reentry during reperfusion, indicating that stabilization of mitochondrial network dynamics is important for preventing post-ischemic arrhythmias. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease".
    Journal of Molecular and Cellular Cardiology 01/2015; 78:90-99. DOI:10.1016/j.yjmcc.2014.09.024 · 4.66 Impact Factor
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    • "During this process, a mitochondrial cluster can reach a critical size (sometimes referred to as “mitochondrial criticality” Aon et al., 2004, 2006) where mitochondria spontaneously self-synchronize, as in a phase transition. So far, investigations strongly support the fact that ROS-induced ROS release is a key player in such inter-mitochondrial communication or coupling (Zorov et al., 2006; Zhou et al., 2010; Nivala et al., 2011). "
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    ABSTRACT: Multi-oscillatory behavior of mitochondrial inner membrane potential ΔΨ m in self-organized cardiac mitochondrial networks can be triggered by metabolic or oxidative stress. Spatio-temporal analyses of cardiac mitochondrial networks have shown that mitochondria are heterogeneously organized in synchronously oscillating clusters in which the mean cluster frequency and size are inversely correlated, thus suggesting a modulation of cluster frequency through local inter-mitochondrial coupling. In this study, we propose a method to examine the mitochondrial network's topology through quantification of its dynamic local clustering coefficients. Individual mitochondrial ΔΨ m oscillation signals were identified for each cardiac myocyte and cross-correlated with all network mitochondria using previously described methods (Kurz et al., 2010a). Time-varying inter-mitochondrial connectivity, defined for mitochondria in the whole network whose signals are at least 90% correlated at any given time point, allowed considering functional local clustering coefficients. It is shown that mitochondrial clustering in isolated cardiac myocytes changes dynamically and is significantly higher than for random mitochondrial networks that are constructed using the Erdös-Rényi model based on the same sets of vertices. The network's time-averaged clustering coefficient for cardiac myocytes was found to be 0.500 ± 0.051 (N = 9) vs. 0.061 ± 0.020 for random networks, respectively. Our results demonstrate that cardiac mitochondria constitute a network with dynamically connected constituents whose topological organization is prone to clustering. Cluster partitioning in networks of coupled oscillators has been observed in scale-free and chaotic systems and is therefore in good agreement with previous models of cardiac mitochondrial networks.
    Frontiers in Physiology 09/2014; 5:329. DOI:10.3389/fphys.2014.00329 · 3.53 Impact Factor
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    • "Through frequency and amplitude modulation oscillatory dynamics may function as a temporal-encoding signaling mechanism, and ROS-induced ROS release (Zorov et al., 2000; Aon et al., 2003; Zhou et al., 2010) act as an effective coupling and synchronizing mechanism of networked mitochondria because it can exert both local and cell-wide influence (Aon et al., 2004). The present work further adds to this picture in that the inverse relationship between the amplitude and frequency components of the oscillatory H2O2 release from mitochondria (Figure 4) includes the spatio-temporal functional interdependence between biochemical processes localized in mitochondrial matrix and extra-matrix compartments as depicted in Figures 1, 6. Specifically, the 3D phase space projection of the dynamics of H2O2 released as a function of other energetic variables (ΔΨm, succinate) (Figure 6) demonstrates the dynamic-functional interrelationships between processes occurring within the same time scale (seconds). "
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    ABSTRACT: The time-keeping properties bestowed by oscillatory behavior on functional rhythms represent an evolutionarily conserved trait in living systems. Mitochondrial networks function as timekeepers maximizing energetic output while tuning reactive oxygen species (ROS) within physiological levels compatible with signaling. In this work, we explore the potential for timekeeping functions dependent on mitochondrial dynamics with the validated two-compartment mitochondrial energetic-redox (ME-R) computational model, that takes into account (a) four main redox couples [NADH, NADPH, GSH, Trx(SH)2], (b) scavenging systems (glutathione, thioredoxin, SOD, catalase) distributed in matrix and extra-matrix compartments, and (c) transport of ROS species between them. Herein, we describe that the ME-R model can exhibit highly complex oscillatory dynamics in energetic/redox variables and ROS species, consisting of at least five frequencies with modulated amplitudes and period according to power spectral analysis. By stability analysis we describe that the extent of steady state-as against complex oscillatory behavior-was dependent upon the abundance of Mn and Cu, Zn SODs, and their interplay with ROS production in the respiratory chain. Large parametric regions corresponding to oscillatory dynamics of increasingly complex waveforms were obtained at low Cu, Zn SOD concentration as a function of Mn SOD. This oscillatory domain was greatly reduced at higher levels of Cu, Zn SOD. Interestingly, the realm of complex oscillations was located at the edge between normal and pathological mitochondrial energetic behavior, and was characterized by oxidative stress. We conclude that complex oscillatory dynamics could represent a frequency- and amplitude-modulated H2O2 signaling mechanism that arises under intense oxidative stress. By modulating SOD, cells could have evolved an adaptive compromise between relative constancy and the flexibility required under stressful redox/energetic conditions.
    Frontiers in Physiology 07/2014; 5:257. DOI:10.3389/fphys.2014.00257 · 3.53 Impact Factor
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