Mitochondria and arrhythmias

Highlights

• We review the mechanisms by which mitochondrial dysfunction causes arrhythmias.

• Mitochondrial dysfunction leads to increased reactive oxidative species production.

• Mitochondrial dysfunction impairs sarcolemmal and sarcoplasmic channel functions.

• Mitochondrial dysfunction results in impaired intracellular cation homeostasis.

• The use of mitochondria-targeted antioxidants might be a novel antiarrhythmic therapy.

Abstract

Mitochondria are essential to providing ATP, thereby satisfying the energy demand of the incessant electrical activity and contractile action of cardiac muscle. Emerging evidence indicates that mitochondrial dysfunction can adversely affect cardiac electrical functioning by impairing the intracellular ion homeostasis and membrane excitability through reduced ATP production and excessive reactive oxygen species (ROS) generation, resulting in increased propensity to cardiac arrhythmias. In this review, the molecular mechanisms linking mitochondrial dysfunction to cardiac arrhythmias are discussed with an emphasis on the impact of increased mitochondrial ROS on the cardiac ion channels and transporters that are critical to maintaining normal electromechanical functioning of the cardiomyocytes. The potential of using mitochondria-targeted antioxidants as a novel antiarrhythmia therapy is highlighted.

Introduction

The normal functioning heart requires coordinated, rhythmic electrical activity and contractile action. At rest, the heart pumps about 280 l of blood throughout the human body per hour, and the energy demand to meet this unceasing action consumes nearly 10% of the total body O₂ uptake [1]. Over 90% of the cellular ATP consumed in the heart is produced by the mitochondria through oxidative phosphorylation (OXPHOS) [2]. As the predominant energy generator in the heart, mitochondria account for ~30% of the volume of cardiac cells, forming a network surrounding the sarcoplasmic reticulum (SR), myofilaments, and t-tubules [3]. It is estimated that one-third of the cardiac ATP generated by mitochondria is used for sarcolemmal and SR ion channels and transporters, which are required for the electrical activity of the cardiac cells [4]. Therefore, mitochondrial dysfunction readily disrupts the cardiac rhythm by depleting energy supply to these channels and transporters [5], [6].

In addition to producing ATP, mitochondria also generate reactive oxygen species (ROS) as a by-product of OXPHOS. It is now widely accepted that in addition to their critical bioenergetic function, mitochondria function as signaling hubs in large part by regulating redox signaling in the cell [7], [8]. Under physiological conditions, trace amount of ROS establish a network of mitochondria-driven signals that integrate metabolism with gene transcription and enzymatic activity [9], [10]. Short-term increases in ROS signals trigger adaptive responses and facilitate preconditioning, increasing cellular and tissue resistance against insult [11], [12]. On the other hand, persistently elevated ROS levels can trigger maladaptive responses and persistent abnormalities that compromise function at the molecular, cellular, and tissue levels [13], [14], [15]; in this regard, excessive production of ROS elicits pathologic changes by altering cellular function and increasing cell death [16]. Emerging evidence has shown that excessive mitochondrial ROS production can impair cardiac excitability by affecting the function of various channels and transporters through direct interaction such as posttranslational redox modification of cysteine (S-glutathionylation, sulfhydration, and S-nitrosation) or tyrosine (nitration) residues [17], [18], [19]. Excessive mitochondrial ROS can also modulate ion channel/transporter function indirectly via associated signaling molecules, such as ROS-sensitive kinases, including calcium–calmodulin-dependent protein kinase (CaMKII), cSrc, and protein kinase C (PKC), or via redox-sensitive transcription factors, such as NF-κB [20], [21], [22].

Mitochondria are also critically involved in the homeostatic regulation of cellular cations such as Ca²⁺, Na⁺, and K⁺, disturbance of which can have important consequences for cardiac contractility, energetics, and electrical activity [23], [24], [25]. There is a complex interrelationship between sarcolemmal and mitochondrial cation regulation. Mitochondria can take up and extrude Ca²⁺, for example, modulating cardiomyocyte function by serving as a dynamic buffer for sarcolemmal Ca²⁺ [26], [27]. Changes in sarcolemmal cation concentration, on the other hand, can influence mitochondrial structure [28], [29], energetics [30], [31], and mitochondria-dependent cell death [32]. Much of the mitochondria–sarcolemma cation interdependence is mediated by the ion channels or transporters located on the inner membrane of mitochondria (see below).

Many central metabolic systems operate totally or partially within the mitochondria. These systems dynamically regulate cellular energetic status and sarcolemmal ATP-sensitive potassium (sarcK_ATP) currents through oscillating mitochondrial membrane potential (∆Ψ_m) in response to the changes in the supply of fuel substrates and O₂ [33], [34], [35]. In the presence of metabolic stress such as myocardial ischemia, depolarization of ∆Ψ_m diminishes mitochondrial ATP production, resulting in the opening of the sarcK_ATP channels, which creates a “current sink” in the myocardium, capable of slowing or blocking cardiac electrical propagation, thereby fomenting arrhythmias (see below) [33], [36].

After a brief review on the ionic basis of cardiac excitability, mitochondrial energetics/ROS production, and mitochondrial/sarcolemmal cation homeostasis, the role of mitochondrial dysfunction in influencing myocyte excitability and cardiac arrhythmogenesis is discussed, with an emphasis on the impact of mitochondrial ROS on sarcolemmal and sarcoplasmic channel/transporter functioning. In addition, the potential antiarrhythmic therapies targeting mitochondrial dysfunction in cardiac diseases are highlighted.