Mitochondrial Reactive Oxygen Species (ROS) and Arrhythmias.

Abstract

In this chapter we analyze the onset of cardiac arrhythmias from the perspective of mitochondrial redox state and energetic metabolism. Significant perturbations in the mitochondrial redox environment trigger mitochondrial membrane potential (ΔΨm) depolarization that under critical conditions can scale up to the whole heart, thereby producing fatal arrhythmias. Utilizing a combined experimental–theoretical approach, we evaluate the processes dynamics at each level of organization involved (molecular, mitochondrial, cardiomyocyte, whole heart) while highlighting their mechanistic interrelationships to explain the appearance of novel emergent properties. Under metabolically stressful conditions, the mitochondrial network of cardiac cells accumulate high level of reactive oxygen species (ROS) attaining a critical state – referred to as mitochondrial criticality. Under criticality, the slightest perturbation triggers a cell-wide collapse of ΔΨm, visualized as a depolarization wave throughout the cell, which is followed by whole cell sustained mitochondrial oscillations in ΔΨm, NADH, ROS, and glutathione. This macroscopic dynamic behavior escalates from the mitochondrion to the organ level driving the heart into catastrophic arrhythmias.