The mechanisms and roles of mitochondria dysfunction in cardiac arrhythmogenesis

线粒体功能障碍在心律失常发生中的机制和作用

• 批准号: 10734432
• 负责人: Dmitry A Terentyev
• 金额: $ 73.01万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734432
• 关键词: Acceleration; Adenovirus Vector; Affect; Aging; Animals; Antioxidants; Arrhythmia; Attenuated; Biochemical; Bioenergetics; Bioprobe; Biosensor; COX7A2L gene; Calcium; Calcium Signaling; Calpain; Cardiac; Cardiovascular Diseases; Cardiovascular system; Catecholaminergic Polymorphic Ventricular Tachycardia; Coupling; Crista ampullaris; Diameter; Down-Regulation; Electrocardiogram; Electron Transport; Elements; Event; Extravasation; Female; Generations; Genetic; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Heritability; Homeostasis; Human; Hyperactivity; Hypertrophy; Inherited; Interruption; Lead; Link; Malignant - descriptor; Maps; Mediating; Membrane Potentials; Metabolic; Mitochondria; Mitochondrial Matrix; Modeling; Modification; Molecular; Molecular Target; Monitor; Muscle Cells; OPA1 gene; Optics; Outcome; Output; Pathologic; Peptide Hydrolases; Physiological; Pilot Projects; Play; Premenopause; Process; Production; Proteins; Proteolysis; Rattus; Reactive Oxygen Species; Respiration; Risk; Role; Ryanodine Receptor Calcium Release Channel; Sex Differences; Signal Transduction; Stress; Structural Protein; Structure; Syndrome; Tachyarrhythmias; Testing; Therapeutic; Thoracic aorta; Tissues; Transmission Electron Microscopy; Ventricular; Ventricular Arrhythmia; Visualization; Workload; calpain inhibitor; calpastatin; fluorescence lifetime imaging; gain of function; heart function; improved; in vivo; insight; loss of function; male; mitochondrial dysfunction; mitochondrial membrane; mortality; novel; novel strategies; oxidation; receptor function; response; restoration; sex; sexual dimorphism; sudden cardiac death; targeted treatment; vector

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.

由于应激诱发的室性快速性心律失常引起的心源性猝死仍然是死亡的主要原因 世界上心室肌细胞（VM）中线粒体代谢输出与细胞内Ca 2+紧密相关 在一个称为兴奋-收缩-生物能量学（ECB）耦合的过程中循环。在这个过程中的干扰 不仅在获得性疾病如心力衰竭（HF）、肥大或衰老中， 遗传性心律失常综合征。在儿茶酚胺能激增期间，即应激和最大工作负荷期间， 细胞内Ca 2+瞬时振幅的增加导致基质[Ca 2 +]内流增加， 生产ATP以满足增加的代谢需求。然而，这也带来了发电量增加的风险。 活性氧（ROS）通过电子传递链（ETC）。这可以克服抗氧化剂 防御和不利地影响Ca 2+处理机制和ryanodine受体（RyR 2），促进Ca 2 + 依赖性心律失常因此，本提案的主要目标是确定新的办法 维持线粒体活性氧和钙离子稳态，改善心脏功能并降低心律失常风险 病态的心脏在初步研究过程中，我们发现， 来自ETC元素的四元超复合物在加速线粒体-ROS产生中起关键作用， 来自肥大大鼠心脏的VM和来自儿茶酚胺能多态性遗传大鼠模型的心脏 室性心动过速（CPVT）。初步研究表明，两种蛋白质表达水平的变化可以 作为不太紧凑的ETC组织的基础，即（1）COX 7 RP，超复合物形成的关键调节剂，和 (2)控制线粒体嵴直径的结构蛋白OPA 1。重要的是，我们发现， 这两种蛋白质的表达水平在健康女性中高于男性，这表明 两性间ECB偶联的差异。因此，提出了两个具体目标。目标1： 确定RyR 2高活性介导的线粒体功能变化的作用和机制。 我们建立了一种独特的CPVT大鼠模型，以测试RyR 2过度活跃的假设， 有助于激活位于线粒体膜间隙的钙依赖性蛋白酶钙蛋白酶 导致OPA 1蛋白水解。目的2：探讨高脂血症的发生机制及其生理意义。 心律失常中的COX 7 RP依赖性线粒体功能障碍与RyR 2过度活跃有关我们 假设COX 7 RP下调是线粒体电子传递缺陷关键因素 心肌肥厚和心力衰竭时线粒体活性氧释放增加， 处理不当