Dynamics of Mitochondrial Redox and Energy Networks: Insights from an Experimental–Computational Synergy - Systems Biology of Metabolic and Signaling Networks - page 113

different compartments whose interaction is mediated by transport processes. If we
zoom in within a set of processes we will find even more detailed networks, and the
dynamics is reflected by fluxes occurring in different compartments, e.g., by
channels and pumps in the plasma membrane, sarcoplasmic reticulum, myofibrils,
and mitochondria.
The molecular view analyzes interactions in biomolecular networks involving
different components which result in varied functional outputs: protein-protein,
genetic expression (multi arrays), regulatory (protein-DNA interactions, combina-
torial transcription factors), and signaling (signal transduction pathways through
protein-protein and protein-small molecule interactions) (Cortassa et al. 2012 ).
From a temporal perspective a highly tuned response exists in energy supply by
mitochondria to the demand by electromechanical processes in the heart operating
in the millisecond range (e.g., action potentials, calcium transients) (Fig. 5.1 ). This
tight match between energy supply and demand can be more readily fulfilled by the
highly synchronized and robust action of mitochondrial networks. In the heart,
mitochondria constitute an extensive subcellular network, which occupies ~30 % of
the heart cell volume, and appears to be wrapped by the sarcoplasmic reticulum and
in close vicinity with the myofilaments and t-tubules. During maximal workload,
the whole ATP pool in the heart cell is turned over in a few seconds, while ~2 % of
that pool is consumed in each heartbeat. Both constancy and flexibility are required
from the mitochondrial network in response to the changing metabolic demand for
supplying a steady output of ATP to fuel contraction, and to adapt the rate of energy
provision. Whereas under normal physiological conditions the availability of
energy is fine-tuned to match changes in energy demand, under stress this is not
the case.
The idea that mitochondria may function as a coordinated network of oscillators
emerged from studies on living cardiomyocytes subjected to metabolic stress. The
network behavior of mitochondria depends on local as well as global coordination
in the cell, and ROS-induced ROS release is a mechanism that was shown to exert
both local and cell-wide influence on the network. Mitochondrial network organi-
zation may be also essential for the temporal organization of the heart rhythm.
Mitochondrial network energetics , or the functioning of mitochondria as
networks, represents an advantageous behavior for its coordinated action, under
normal physiology, provides overall and usual robustness despite occasional failure
in a few nodes, and improves energy supply during a swiftly changing demand
(Aon and Cortassa 2012 ). Mitochondrial network energetics along with its remark-
able nonlinear properties together with those of the whole heart itself set the stage
for the appearance of critical phenomena and bifurcations leading to self-organized,
emergent behavior. An amazing example of the latter is given by the existence, at
critical points (mitochondrial criticality), of emergent macroscopic self-organized
behavior escalating from the subcellular to the whole heart, eventually leading to
the death of the animal. The demonstration of the involvement of mitochondrial
oscillations in reperfusion-related arrhythmias after ischemic injury, and of their