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.

应激性室性心律失常导致的心源性猝死仍然是死亡的主要原因 在世界上。心室肌细胞 (VM) 中的线粒体代谢输出与细胞内 Ca2+ 紧密相关 循环过程称为兴奋-收缩-生物能量学 (ECB) 耦合。这个过程中的干扰 不仅在心力衰竭（HF）、肥厚或衰老等后天性疾病中会导致心律失常，而且在 还有遗传性心律失常综合征。在儿茶酚胺能激增期间，即压力和最大工作量时， 细胞内 Ca2+ 瞬态幅度的增加导致基质 [Ca2+] 流入增加并加速 ATP 生产以满足增加的代谢需求。然而，它伴随着发电量增加的风险 通过电子传输链 (ETC) 产生活性氧 (ROS)。这可以克服抗氧化剂 防御并对 Ca2+ 处理机制和兰尼碱受体 (RyR2) 产生不利影响，促进 Ca2+ 依赖性心律失常。因此，当前提案的主要目标是确定新方法 维持线粒体 ROS 和 Ca2+ 稳态，改善心脏功能并降低心律失常风险 患病的心。在初步研究过程中，我们发现减少了 来自 ETC 元素的四元超复合物在加速 mito-ROS 产生中起着关键作用 来自肥大大鼠心脏和来自儿茶酚胺能多态性遗传大鼠模型的心脏的VM 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 是不太紧凑的 ETC 组织的基础，即 (1) COX7RP，超复合物形成的关键调节因子，以及 (2)结构蛋白OPA1，控制线粒体嵴直径。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比男性中更高，这表明了根本性的 性别之间 ECB 耦合的差异。据此，提出了两个具体目标。目标 1： 确定 RyR2 过度活跃介导的线粒体功能变化的作用和机制。 我们创建了一个独特的 RyR2 功能增益大鼠 CPVT 模型来检验 RyR2 过度活跃的假设 有助于激活位于线粒体膜间隙中的 Ca2+ 依赖性蛋白酶钙蛋白酶 导致 OPA1 蛋白水解。目标 2：确定其机制和生理意义 心律失常中 COX7RP 依赖性线粒体功能障碍与 RyR2 过度活跃有关。我们 假设 COX7RP 下调是线粒体电子传递缺陷的关键因素 心脏肥大和衰竭时线粒体 ROS 排放增加，加剧促心律失常 Ca2+i 处理不当。