Mitochondrial Dysfunction in Cardiac Arrhythmias

Figures

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  Figure 1. Summary of molecular mechanisms of arrhythmias. Cardiac arrhythmias can be divided to abnormal impulse formation (also termed as focal activity) and conduction disturbances. Automaticity problems involve both enhanced and reduced automaticity, which are the etiology of sinus tachycardia and bradycardia, respectively. Early and late after depolarization is the common mechanism of both atrial and ventricular premature complexes. Reentrant tachyarrhythmias as a conduction disturbance usually involve both substrate (reduced conduction velocity) and trigger where an impulse circles back to re-excite the myocardium through retrograde conduction via the area of functional block. Conduction delay/block also belongs to conduction disturbances.

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  Figure 2. Holistic overview of sarcolemmal and intracellular ion balances in cardiomyocytes and their alterations under mitochondrial dysfunction. Sarcoplasmic reticulum (SR) oversees Ca2+ storage and releasing into the cytosol. The main Ca2+ release channel in cardiomyocytes is RyR2 while SERCA recycles Ca2+ during diastole. ROS increase RyR opening and reduce SERCA recycling via decreased ATP production, thereby causing Ca2+ overload. Increased inward Na+ from HCN channel can reverse the Na+/Ca2+ exchanger activity and subsequently lead to intracellular Ca2+ overload and arrhythmias. Moreover, under excessive ROS generation, a net decrease in K+ exit along with increased inward late Na+ current can cause delayed repolarization and prolonged action potential duration (APD). Sarcoplasmic reticulum mitochondrial contacts (SRMCs) are another important location of calcium transport regulation. The IP3R/GRP75/VDAC complex interacts with MCU to relocate Ca2+ into the mitochondria matrix. Brown dashed arrows represent directions of ion currents; black solid arrows represent increased or suppressed channel activities.

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  Figure 3. Overview of mitochondrial proteins in cardiac physiology and pathophysiology. A variety of proteins are involved in the functional maintenance of mitochondria. CAMKII activates MCU and allows mitochondrial Ca2+ overload, which contributes to ROS production. ROS, along with related mitochondrial DNA damage, contribute to the activation of inflammasomes and subsequent cell death. Structural remodeling induced by inflammatory cytokines produced by inflammasomes follows. On the other hand, the increased level of nitric oxide via activation of angiotensin II type 2 receptor, elevation of mitochondrial connexin located on the inner mitochondrial membrane, and augmentation of humanin peptides all contribute to the mitigation of ROS.