The mechanisms and roles of mitochondria dysfunction in cardiac arrhythmogenesis

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Sudden cardiac death due to stress-induced ventricular tachyarrhythmias remains the major cause of mortality in the world. Mitochondrial metabolic output in ventricular myocytes (VMs) is tightly linked to intracellular Ca2+ cycling in a process called excitation-contraction-bioenergetics (ECB) coupling. Disturbances in this process contribute to arrhythmias not only in acquired conditions such as heart failure (HF), hypertrophy or aging, but in heritable arrhythmia syndromes as well. During catecholaminergic surge, i.e. stress and maximum workload, an increase in intracellular Ca2+ transient amplitude results in increased matrix [Ca2+] influx and accelerated ATP production to meet increased metabolic demand. However, it comes with the risk of increased generation of reactive oxygen species (ROS) by the electron transport chain (ETC). This can overcome antioxidant defenses and adversely affect Ca2+ handling machinery and the ryanodine receptor (RyR2), promoting Ca2+ dependent arrhythmia. Therefore, the main objective of current proposal is the identification of new approaches to maintain mitochondrial ROS and Ca2+homeostasis to improve cardiac function and reduce arrhythmic risk in diseased hearts. In the course of preliminary studies, we discovered that a reduction in the formation of quaternary supercomplexes from the elements of ETC plays a key role in accelerated mito-ROS production in VMs from hypertrophic rat hearts and hearts from genetic rat model of catecholaminergic polymorphic ventricular tachycardia (CPVT). Pilot studies revealed that changes in expression levels of two proteins can underlie less compact ETC organization, namely (1) COX7RP, a key regulator of supercomplex formation, and (2) structural protein OPA1 which controls mitochondria cristae diameter. Importantly, we discovered that expression levels of both these proteins are higher in healthy females vs males, suggesting fundamental differences in ECB coupling between sexes. Accordingly, two specific aims are proposed. Aim 1: To determine the role and mechanisms of RyR2 hyperactivity-mediated changes in mitochondria function. We created a unique gain-of RyR2 function rat model of CPVT to test the hypothesis that RyR2 hyperactivity contributes to activation of Ca2+-dependent protease calpain residing in mitochondria intermembrane space leading to OPA1 proteolysis. Aim 2: To determine the mechanisms and physiological significance of COX7RP-dependent mitochondrial dysfunction in cardiac arrhythmias linked to RyR2 hyperactivity. We hypothesize that COX7RP downregulation is the key contributor to the deficient mitochondria electron transport and increased mito-ROS emission in cardiac hypertrophy and failure exacerbating pro-arrhythmic Ca2+i mishandling.