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A reaction-diffusion model of ROS-induced ROS release in a mitochondrial network.

Zhou L, Aon MA, Almas T, Cortassa S, Winslow RL, O'Rourke B - PLoS Comput. Biol. (2010)

Bottom Line: In addition, we present novel experimental evidence, obtained in permeabilized cardiomyocytes, confirming that DeltaPsi(m) depolarization is mediated specifically by O2.-).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.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

ABSTRACT
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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Plot of membrane potential of selected mitochondrial groups that display limited cycle oscillations.Guinea-pig ventricular myocyte was loaded with TMRM and CM-DCF and then partially permeabilized with 25µg ml−1 saponin as described in Materials and Methods. Image frames were collected every 3.5 seconds using a two-photon laser scanning fluorescence microscope. See also the supplemental materials Video S1.
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pcbi-1000657-g006: Plot of membrane potential of selected mitochondrial groups that display limited cycle oscillations.Guinea-pig ventricular myocyte was loaded with TMRM and CM-DCF and then partially permeabilized with 25µg ml−1 saponin as described in Materials and Methods. Image frames were collected every 3.5 seconds using a two-photon laser scanning fluorescence microscope. See also the supplemental materials Video S1.

Mentions: The original ROS-dependent mitochondrial oscillator model [16], which was based on experimental observations, considered cytoplasmic O2.− as the primary free radical species that would increase in IMAC open probability in an autocatalytic process. H2O2 was ruled out because superoxide dismutase mimetics, which should enhance H2O2 accumulation, suppressed the oscillations in ΔΨm [8]. To test the assumption that O2.− could directly trigger IMAC opening we applied increasing concentrations of KO2 to partially permeabilized myocytes. Increasing the exogenous cytoplasmic KO2 concentration, as a source of O2.−, from 10 to 20 µM, elicited progressive ΔΨm depolarization and increased the rate of mitochondrial O2.− accumulation (Fig. 5A and 5B). Reversible ΔΨm depolarizations were observed at intermediate concentrations of KO2 (10 to 20 µM, Video S1 and Fig. 6). However, exposure of the cell to 30 µM KO2 induced an irreversible collapse of ΔΨm, accompanied by the complete release of the O2.− sensor indicative of permeability transition pore (PTP) opening (Fig. 5A, bottom row; see also Supplemental Materials Video S2).


A reaction-diffusion model of ROS-induced ROS release in a mitochondrial network.

Zhou L, Aon MA, Almas T, Cortassa S, Winslow RL, O'Rourke B - PLoS Comput. Biol. (2010)

Plot of membrane potential of selected mitochondrial groups that display limited cycle oscillations.Guinea-pig ventricular myocyte was loaded with TMRM and CM-DCF and then partially permeabilized with 25µg ml−1 saponin as described in Materials and Methods. Image frames were collected every 3.5 seconds using a two-photon laser scanning fluorescence microscope. See also the supplemental materials Video S1.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2813265&req=5

pcbi-1000657-g006: Plot of membrane potential of selected mitochondrial groups that display limited cycle oscillations.Guinea-pig ventricular myocyte was loaded with TMRM and CM-DCF and then partially permeabilized with 25µg ml−1 saponin as described in Materials and Methods. Image frames were collected every 3.5 seconds using a two-photon laser scanning fluorescence microscope. See also the supplemental materials Video S1.
Mentions: The original ROS-dependent mitochondrial oscillator model [16], which was based on experimental observations, considered cytoplasmic O2.− as the primary free radical species that would increase in IMAC open probability in an autocatalytic process. H2O2 was ruled out because superoxide dismutase mimetics, which should enhance H2O2 accumulation, suppressed the oscillations in ΔΨm [8]. To test the assumption that O2.− could directly trigger IMAC opening we applied increasing concentrations of KO2 to partially permeabilized myocytes. Increasing the exogenous cytoplasmic KO2 concentration, as a source of O2.−, from 10 to 20 µM, elicited progressive ΔΨm depolarization and increased the rate of mitochondrial O2.− accumulation (Fig. 5A and 5B). Reversible ΔΨm depolarizations were observed at intermediate concentrations of KO2 (10 to 20 µM, Video S1 and Fig. 6). However, exposure of the cell to 30 µM KO2 induced an irreversible collapse of ΔΨm, accompanied by the complete release of the O2.− sensor indicative of permeability transition pore (PTP) opening (Fig. 5A, bottom row; see also Supplemental Materials Video S2).

Bottom Line: In addition, we present novel experimental evidence, obtained in permeabilized cardiomyocytes, confirming that DeltaPsi(m) depolarization is mediated specifically by O2.-).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.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus