Mitochondria and arrhythmias

There is a clear relationship between cardiac mechanical dysfunction and arrhythmogenesis, and yet the mechanistic link is unknown. Mechanical dysfunction is accompanied by mitochondrial dysfunction, and in this review, we will discuss some of the ways mitochondrial dysfunction can lead to arrhythmogenesis, thereby providing a link between mechanical dysfunction and arrhythmias. Mitochondria occupy around 30% of the mammalian myocardium by volume and are responsible for over 90% of cardiac ATP production1. In addition to energy production, mitochondria have been implicated as critical organelles involved in ion channel regulation, heat maintenance, apoptotic function, and regulation of reactive oxygen species (ROS)2. A growing field of research, coined mitochondrial medicine, is aimed at modifying mitochondrial function, in particular the generation of ROS, to alleviate disease burden attributed to mitochondrial stress2;3. The aim of this review is to discuss the role of mitochondrial dysfunction in arrhythmogenesis and to posit new antiarrhythmic therapies based on ameliorating mitochondrial dysfunction in cardiac disease. New information on mitochondrial regulation of sodium channels, potassium channels, and connexons will be discussed. Calcium handling and the mitochondrial permeability transition pore, both of which contribute to arrhythmogenesis and tissue injury following mitochondrial distress, have been reviewed elsewhere. The mitochondria are organelles with two membranes that create two compartments: the intermembrane space and the mitochondrial matrix. Mitochondria function as key regulators of metabolism, utilizing oxygen and dietary substrates to generate ATP via oxidative phosphorylation (OXPHOS). During OXPHOS, electrons are collected from the oxidation of carbohydrates and fats to allow the production of reducing equivalents NADH and FADH2. These reducing equivalents transfer their electrons to the electron transport chain (ETC) complexes along the inner mitochondrial membrane. As the electrons flow through the complexes of the ETC, H+ is driven out of the mitochondrial matrix and sequestered into the intermembrane space. This creates a strongly negative mitochondrial membrane potential designated as Δψm, that can be utilized to help target drugs to the mitochondria. Movement of H+ down the proton-gradient across the inner membrane drives the final complex of the ETC, ATP synthase, which converts ADP to ATP. As a by-product of OXPHOS, reactive oxygen species (ROS) are often produced. Incomplete reduction or a surplus of electrons in the ETC can result in partially reduced oxygen molecules, creating the reactive intermediate superoxide (O2−). The mitochondrial antioxidant protein, manganese superoxide dismutase (MnSOD), is responsible for converting O2− to H2O2, which can be further broken down by catalase. Mitochondrial ROS production is elevated beyond MnSOD’s antioxidant capacity in a wide range of diseases, including diabetes, metabolic syndrome, cancer, and cardiomyopathy, and aging3. This mitochondrial stress results in the build-up of deleterious metabolites, such as NADH and ADP, and depletion of antioxidant defenses, such as glutathione4;5. Recent works in cardiology have implicated mitochondrial stress in arrhythmogenesis, allowing a potential new avenue for therapeutic approach.