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 cardiomyoyte 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.

Age‐dependent electrocardiographic changes in Pgc‐1β deficient murine hearts

“…These had accompanied either fibrotic change or reduced Na + currents resulting from Nav1.5 deficiency in Scn5a +/ − 32, 33, 45 and Scn5a +/ΔKPQ ,21 or secondary to Ca 2+ handling abnormalities in RyR2‐P2328S hearts 44, 46, 47. These findings are also compatible with reports that mitochondrial abnormalities could alter I K and therefore result in current‐load mismatch 6, 30…”

“…They also affect ryanodine receptor function alterations in which affect surface membrane excitability and intracellular Ca 2+ homeostasis 27, 28, 29. Mitochondria are also the main cardiomyocyte ATP source and ATP/ADP depletion increases sarcolemmal ATP‐sensitive K + channel (sarcK ATP ) open probabilities affecting action potential duration (APD), effective refractory period (ERP) and heterogenous current sinks potentially causing current‐load mismatch 30. These cellular mechanisms could in turn potentially give rise to potentially pro‐arrhythmic effects on cell‐cell coupling,31 AP conduction25 and AP repolarisation 26.…”

A technical review of optical mapping of intracellular calcium within myocardial tissue

“…Even though fura 4F has not yet been used in optical mapping experiments, sophisticated multiparametric optical mapping systems are being developed for ratiometric imaging of both high-and low-affinity Ca 2ϩ probes (36,56). Future studies of myocardial metabolism, where changes in Ca i 2ϩ , mitochondrial redox state, and mitochondrial membrane potential are measured (2,39,91,98), would certainly benefit from accurate measurements of relative changes in Ca i 2ϩ using ratiometry. Quantification of nonratiometric signals.…”

High-fat, low-carbohydrate diet promotes arrhythmic death and increases myocardial ischemia-reperfusion injury in rats

“…Mitochondria continually may undergo fusion and fission [regulated by proteins including mitofusin-1, 2 (Mfn1, 2), optic atrophy 1 (Opa1), dynamin-related protein 1 (Drp1), and fission1 (Fis1)], and these processes affect mitochondrial DNA stability, respiratory capacity, response to cellular stress, and mitophagy (7,44). Mitochondrial derangements may also lead to lethal arrhythmias through activation of a number of ion channels under conditions of oxidative stress (1,6). As an example, there is emerging interest in the stromal interaction molecule-1 (STIM1)/Orai-mediated store-operated Ca 2ϩ entry (SOCE), which facilitates the influx of Ca 2ϩ from the extracellular space, resulting in a sustained increase in cytosolic Ca 2ϩ levels, and refills the calcium stores of the sarcoplasmic reticulum (SR) (14).…”