Mitochondria are sources of metabolic sink and arrhythmias

Abstract

Mitochondria have long been recognized for their central role in energy transduction and apoptosis. More recently, extensive work in multiple laboratories around the world has significantly extended the role of cardiac mitochondria from relatively static arbitrators of cell death and survival pathways to highly dynamic organelles that form interactive functional networks across cardiomyocytes. These coupled networks were shown to strongly affect cardiomyocyte responses to oxidative stress by modulating cell signaling pathways that strongly impact physiological properties. Of particular importance is the role of mitochondria in modulating key electrophysiological and calcium cycling properties in cardiomyocytes, either directly through activation of a myriad of mitochondrial ion channels or indirectly by affecting cell signaling cascades, ATP levels, and the over-all redox state of the cardiomyocyte. This important recognition has ushered a renewed interest in understanding, at a more fundamental level, the exact role that cardiac metabolism, in general and mitochondria, in particular, play in both health and disease. In this article, we provide an overview of recent advances in our growing understanding of the fundamental role that cardiac mitochondria play in the genesis of lethal arrhythmias.

Figure 1

Schematic of key energy sensitive ion channels that can promote cell survival, death, or arrhythmias.

Figure 2. Spatio-temporal fluctuations of Δψ_m during global ischemia (Adapted from Figure 4, Lyon et al. J Mol Cell Cardiol. 2010, PMID: 20624394)

Successive contour maps of normalized Δψ_m (above) and its first derivative (below) acquired at 10, 40, 70, and 180 seconds following the onset of global no-flow ischemia in a representative rat heart. These data illustrate the presence of spatially and temporally discordant kinetics of Δψ_m that exist ahead of the main depolarization wave of Δψ_m collapse, which actively propagates across the heart. Color scale: a) Δψ_m contour maps: baseline (black), depolarization (red), hyperpolarization (yellow); b) δΔψ_m/δt contour maps: baseline (black), positive slopes (turquoise), negative slopes (purple).