Cardiac mitochondria and arrhythmias

Abstract

Despite a high prevalence of sudden cardiac death throughout the world, the mechanisms that lead to ventricular arrhythmias are not fully understood. Over the last 20 years, a growing body of evidence indicates that cardiac mitochondria are involved in the genesis of arrhythmia. In this review, we have attempted to describe the role that mitochondria play in altering the heart's electrical function by introducing heterogeneity into the cardiac action potential. Specifically, we have focused on how the energetic status of the mitochondrial network can alter sarcolemmal potassium fluxes through ATP-sensitive potassium channels, creating a 'metabolic sink' for depolarizing wave-fronts and introducing conditions that favour catastrophic arrhythmia. Mechanisms by which mitochondria depolarize under conditions of oxidative stress are characterized, and the contributions of several mitochondrial ion channels to mitochondrial depolarization are presented. The inner membrane anion channel in particular opens upstream of other inner membrane channels during metabolic stress, and may be an effective target to prevent the metabolic oscillations that create action potential lability. Finally, we discuss therapeutic strategies that prevent arrhythmias by preserving mitochondrial membrane potential in the face of oxidative stress, supporting the notion that treatments aimed at cardiac mitochondria have significant potential in attenuating electrical dysfunction in the heart.

Figure 1

Cascade of events where the opening of energy-dissipating anion channels in the mitochondrial inner membrane (IMM) leads to a depolarization of the mitochondrial network, opening of sarcK_ATP channels, and ultimately transition to arrhythmia in the intact organ. (A) Schematic depiction of the IMM under conditions of normoxia associated with sinus rhythm (left) and during metabolic stress (right). Matrix oxidation is characterized by glutathione oxidation and opening of IMAC, which collapses the ΔΨ_m, leading to ROS-induced ROS release in the mitochondrial network. Structures for IMAC and the PTP are speculative and based on previous reports.^, (B) Two-photon images of ΔΨ_m in an intact guinea pig heart under normoxic (left) and oxidative (right) conditions. (C) Recordings of LV pressure (red trace) and ECG in a guinea pig heart subjected to normoxic and oxidative conditions. The time course for (B) and (C) are similar for both images, indicating that collapse of ΔΨ_m was accompanied by transition to fatal ventricular arrhythmia. Panels (B) and (C) are reprinted from Brown et al. with permission from Elsevier.