📒 Zhou 2012

Cardiac mitochondrial network excitability: insights from computational analysis1



  • Mitochondria are the hubs of cellular metabolic and signaling pathways, a highly ordered lattice in cardiac cells
    • e.g. Ca2+ and reactive oxygen species (ROS) signaling
  • mitochondrial ROS-induced ROS release (RIRR) from the activation of the inner membrane anion channel (IMAC)
  • frequency domain analysis of ΔΨm provided evidence for correlated oscillations of ΔΨm spanning a wide frequency range even under physiological conditions
  • the frequency of ΔΨm oscillation depends inversely on cluster size

ROS source and target

  • up to 0.5–2% of electrons flowing through the electron transport chain are partially reduced to form superoxide anion (O2·−), from complex I and III
  • Elevated ROS can increase the permeability of mitochondrial outer membrane, facilitating the release of cytochrome c that activates the cellular apoptotic process (mPTP opening)
  • ROS overload could also cause a depletion of the intracellular redox pool (6) and decrease of ATP production

Ca2+ handling and signaling

  • ruthenium red-sensitive Ca2+ uniporter (MCU) is the primary route for Ca2+ entry into the mitochondrial matrix
  • increase in matrix Ca2+ is important for stimulating CAC and OXPHOS
  • mitochondrial Ca2+ overload can trigger mPTP opening and persistent mitochondrial depolarization
  • LCC, RyR, SERCA are sensitive to ROS (and CaMKII)
  • mitochondria can function as a Ca2+ sink by taking up a large amount of Ca2+, allowing matrix free Ca2+ to be kept in the μM range, which minimizes the osmotic effects of Ca2+ uptake

Mitochondrial Network Excitability Induced by IMAC-Mediated RIRR

  • Mitochondrial ROS generation is a self-amplifying process (RIRR) that can be triggered by intracellular or exogenous ROS sources
  • A local laser flash which triggers a burst of ROS production in a small number of mitochondria is followed by synchronized, cell-wide oscillations of ROS, ΔΨm, NADH, and GSH/GSSG
  • A few initially depolarized mitochondria (e.g., triggered by local photooxidation) recruit their neighbors within a cluster through ROS diffusion and RIRR

Model simulation

At each node (i,j): $$ V(k)_{i, j} \frac{\mathrm{d} \mathrm{C}(k)_{i, j} }{\mathrm{dt} } =R(k)_{i, j} + J(k)_{i, j} $$

reaction and diffusion according to the partial differential equation $$ \frac{\partial C_{O_{2} i}(x, y, t)}{\partial t}=D_{O_{2} i}\left(\frac{\partial^{2} C_{O_{2}}(x, t)}{\partial x^{2}}+\frac{\partial^{2} C_{O_{2}}(y, t)}{\partial y^{2}}\right)+f\left(C_{O_{2}^{-i}}, t\right) $$ Using von Neumann boundary condition

  • local diffusion (1 to 2 μm distances between neighboring mitochondria) of ROS can give long range (∼100 μm cellular length) global behavior
  • the velocity of the wave and the rate of depolarization do not decline with distance from the site of wave origin

RIRR, ROS diffusion, and wave propagation

  • In the single mitochondrion model (29), RIRR occurs when O2·− produced from the electron transport chain builds up in the matrix and subsequently leaks out to a level that triggers IMAC opening via cytoplasmic activation site
  • to elicit the whole network response, this local ROS burst must reach the neighboring mitochondria at concentration above the threshold to active their IMACs

  • Oscillation depending on ROS diffusion rate or the scavenging capacity (local ROS concentration)

Mitochondrial excitability: network versus single mitochondrion

  • In the single mitochondrion model of RIRR developed by Cortassa et al. (29), oscillation occurs when there is a bifurcation in the dynamics of the model, creating upper (polarized) and lower (depolarized) branches of the steady state
    • only when key parameters are within the oscillatory domain (e.g., small ROS scavenging, etSOD, or large ROS production, shunt)
  • For the network model, however, entrainment of mitochondria that would not normally oscillate is possible
  • individual mitochondria might be oscillating at high frequencies and low amplitudes at all times but become entrained under stress to produce network-wide large amplitude, slow oscillations
  • Thus, a mitochondrion does not necessarily need to be in an “oscillatory parametric domain” to oscillate; the determining factor is the surrounding ROS concentration
  • Stochastic gating of IMAC channel resulted in flickering of ΔΨm, and when the mitochondria were initialized with high sox production rates, coupling occurred in the network, resulting in propagating waves and slower periodic oscillations at the whole cell level (Nivala et al.)

Other potential mechanisms participating in IMAC-mediated mitochondrial oscillations

  • IMAC is permeable to a variety of inorganic (e.g., Cl− and Pi) and organic (e.g., citrate3−, malate2− and ATP4−) anions
  • there is no direct experimental evidence to implicate free Mg2+ depletion and pH changes as a trigger of the RIRR

Mitochondrial Network Excitability Induced by mPTP-Mediated RIRR

  • slow depolarization wave (<0.1 μm/s) compared to RIRR (∼25 μm/s)
  • their model was able to simulate both IMAC-mediated and mPTP-mediated mitochondrial oscillations and depolarization wave propagation, depending on how much O2·− production (Kshunt) was induced by external factors
    • low Kshunt: IMAC-mediated RIRR
    • high Kshunt: opening of mPTP
  • opening of mPTP eventually led to irreversible ΔΨm depolarization
  • the mitochondrial network can exhibit two different types of excitabilities, fast waves induced by the IMAC-mediated RIRR (triggered by O2·−) and slower waves caused by mPTP-mediated RIRR (triggered by H2O2) processes

  • Caveat: the mechanism of activation of energy-dissipating ion channels in the mitochondrial inner membrane are not well understood and the molecular structures of IMAC and PTP have not been determined

Agent-Based Model of Mitochondrial Network Excitability

  • Park et al: mitochondrial network organization could significantly affect intracellular ROS propagation profiles and cellular sensitivity to oxidative stress
    • CMC: lattice: SOX
    • Neuron: irregular: H2O2

Mitochondrial Excitability Induced by mPTP-Mediated Mitochondrial Ca2+-Induced Ca2+ Release

  • Mitochondrial excitability through Ca2+-induced Ca2+ release (mCICR)
  • Selivanov et al. developed a kinetic model of mitochondria that composes of Ca2+ uniporter, pH-gated mPTP, and respiratory chain
  • Oster et al: modified the Magnus-Keizer model by incorporating the PTP and mitochondrial pH buffering systems.
  • There is still little experimental evidence to indicate that mCICR-mediated mitochondrial excitability occurs in intact cells or in vivo.

Mitochondrial Network Excitability and Cardiac Pathology

  • decrease in ATP-to-ADP ratio is the activation of sarcolemmal ATP-sensitive K+ (KATP) channels, causing shortening of action potential duration
  • Oxidative stress also influences cytosolic Ca2+ transients: LCC, RyR, SERCA

  1. Zhou L, O’Rourke B. Cardiac mitochondrial network excitability: insights from computational analysis. Am. J. Physiol. Heart Circ. Physiol. 2012;302(11):H2178-89. doi:10.1152/ajpheart.01073.2011. PMC3378299↩︎