Dynamics of Mitochondrial Redox and Energy Networks: Insights from an Experimental–Computational Synergy - Systems Biology of Metabolic and Signaling Networks - page 127

complete release of the O 2 . sensor, indicative of permeability transition pore
(PTP) opening (Fig. 5.9a ).

5.4.4 Propagation of Depolarization Through ROS-Induced
ROS Release (RIRR)

RIRR as the basic mechanism of propagation of ΔΨ m depolarization and O 2 .
release was also demonstrated in the 2D RD-RIRR mitochondrial network model
(Zhou et al. 2010 ). Consisting of five hundred (10 50) mitochondria, the 2D

RD-RIRR model was parametrically initialized to represent a condition of high
oxidative stress to simulate a mitochondrial network at criticality. Approximately
1 % (6 out of 500) of the mitochondrial network was induced to undergo depolari-
zation (Fig. 5.8b ). A local increase in O 2 . concentration and depolarization of
ΔΨ m in this area was evident, similar to those processes observed in experiments in
which we applied a localized laser flash to a fraction of the mitochondrial network
(Fig. 5.4 ). ΔΨ m depolarization propagated outward in all directions from the six

perturbed mitochondria and then appeared as a longitudinal wave as the edges of
the array were encountered (Fig. 5.8b , model left panel). Importantly, a wave of
increased O 2 . accompanied the

ΔΨ m depolarization wave (Fig. 5.8b , model right

panel).
Moreover, the model further contributed to our understanding by showing that
(1) local gradients of cytoplasmic O 2 . , determined by diffusion and scavenger
capacity, play a significant role in determining the rate of propagation of the

ΔΨ m
depolarization and repolarization waves; and (2) by uncovering a novel aspect of
the synchronization mechanism, i.e., that clusters of mitochondria that are in a state
characteristic of the oscillatory domain of the parametric space can entrain
mitochondria that would otherwise display stable dynamics (Zhou et al. 2010 ).
While focusing on a specific mechanism of RIRR (i.e., IMAC-mediated), the
model results provided general theoretical support for mitochondrial communica-
tion occurring by way of O 2 . diffusion. The RD-RIRR model simulations confirm
that O 2 . diffusion occurring locally between neighboring mitochondria over a
distance of a few microns is sufficient for propagation and synchronization of
ΔΨ m depolarization over a larger distance (Aon et al. 2004a ; Zhou et al. 2010 ).

5.5 Third Iterative Loop: Mitochondrial Network Redox
Energetics Escalates from Subcellular to Cellular Level

The experimental studies had shown that laser flash-induced cell-wide mitochon-
drial oscillations in isolated cardiomyocytes produced shortening of the cellular
action potential (AP) (Akar et al. 2005 ; Aon et al. 2003 ). The collapse of

ΔΨ m