Ca signaling cross-talk from SR to mitochondria in heart muscle

Ca 信号从 SR 到心肌线粒体的串扰

• 批准号: 9764466
• 负责人: Jianjie Ma
• 金额: $ 65.3万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764466
• 关键词: Ablation; Acute; Affect; Architecture; Arrhythmia; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cations; Cells; Complementary DNA; Coupling; Crystallization; Cultured Cells; Defect; Disease; Electron Microscopy; Endoplasmic Reticulum; Epithelial Cells; Functional disorder; Genes; Genetic; Health; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Homeostasis; Human; Human Genome; Hypertension; Ion Channel; Ions; Isoproterenol; Knock-out; Link; Mediating; Membrane; Mitochondria; Movement; Mus; Muscle Cells; Mutagenesis; Mutation; Myocardial dysfunction; Myocardium; Names; Neonatal; Operative Surgical Procedures; Osteogenesis Imperfecta; Pathologic; Pathology; Patients; Peptides; Permeability; Phase; Physiological; Physiology; Protein Isoforms; Proteins; RNA Interference; Regulation; Research; Role; RyR2; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Signal Transduction; Skeletal Muscle; Smooth Muscle; Stress; Structure; System; Tail; Testing; Tissues; Toxic effect; Transgenic Organisms; biological adaptation to stress; bone; cardiogenesis; cell type; constriction; coronary fibrosis; design; experimental study; heart function; in vivo; mRNA Differential Displays; mitochondrial dysfunction; mouse genome; mutant; novel; receptor; reconstitution; respiratory; skeletal; synthetic peptide

Project Summary Mitochondria and sarcoplasmic reticulum (SR) form close interfaces in cardiomyocytes where the propagation of Ca signals from SR to mitochondria contributes to heart function under physiologic and pathologic conditions. TRIC is a novel class of trimeric intracellular cation channels located at the SR or endoplasmic reticulum (ER) of multiple cell types, which function as counter-ion channels that allow flow of K ions into the SR/ER during the acute phase of Ca release. Genetic ablations or mutations of TRIC channels are associated with hypertension, heart disease, respiratory defects and brittle bone disease. The recent crystal structure of TRIC proteins confirms the homotrimeric architecture of a cation channel. Within the human and mouse genomes, there are two TRIC isoforms, TRIC-A and TRIC-B, that display differential functions in regulation of Ca signaling in excitable and non-excitable cells. While our past research efforts primarily focused on understanding the physiological function for TRIC-A in skeletal and smooth muscle and to a lesser extent the role of TRIC-B in epithelial cells, the role of TRIC in cardiac physiology and disease remains largely unexplored. Here we present evidence that TRIC-A, in addition to modulation of the SR permeability to K ions, functions as an integral component of the physiological control mechanism of Ca signaling in cardiac muscle. We found that the carboxyl-tail domain of TRIC-A interacts with the RyR2 channel to directly modulate Ca release from the SR. The TRIC-A-/- mice develop arrhythmia, severe cardiac hypertrophy and fibrosis following isoproterenol treatment or transverse aortic constriction (TAC) surgery. Isolated TRIC-A-/- cardiomtocytes display mitochondria dysfunction that likely reflects SR Ca overload-induced mitochondria toxicity under stress conditions. As uncontrolled Ca release has been implicated in mitochondrial dysfunction in cardiac pathology, we hypothesize that “TRIC interaction with RyR2 modulates SR Ca release and crosstalk with mitochondria. Absence of TRIC leads to Ca overload inside SR and causes stress-induced Ca toxicity to mitochondria. The dysregulated SR-mitochondria crosstalk contributes to the development of heart failure”. We further propose that targeting TRIC- mediated SR-mitochondria crosstalk represents a novel means for treatment of cardiovascular diseases. Our experiments designed in this project contain two specific aims: Aim 1 - to define the functional interaction between TRIC-A/B and RyR2 in regulating the cross-talk of Ca signaling from SR to mitochondria in cardiomyocytes under physiologic and pathologic conditions; and Aim 2 - to elucidate the in vivo role of TRIC-A in mediating stress-induced changes in heart function.

项目摘要 线粒体和肌质网（SR）在心肌细胞中形成紧密界面，其中 从SR到线粒体的CA信号传播在生理和 病理状况。 Tric是位于SR的新型三聚体细胞内阳离子通道 多种细胞类型的内质网（ER），它们充当反离子通道，允许 在Ca释放的​​急性阶段，K离子流入SR/ER。遗传消融或突变 三位通道与高血压，心脏病，呼吸缺陷和脆性骨骼有关 疾病。最新的三位蛋白晶体结构证实了A的同型结构 阳离子通道。在人类和小鼠基因组中，有两个三合一同工型，Tric-A和 TRIC-B，在令人兴奋和不可驱散的CA信号调节中显示出差异功能 细胞。而我们过去的研究工作主要集中于理解 骨骼和平滑肌中的Tric-A，在较小程度上Tric-B在上皮细胞中的作用， Tric在心脏生理和疾病中的作用在很大程度上仍然是出乎意料的。在这里我们提供证据 除了调节对k离子的SR渗透性外，Tric-A还起到了积分 心肌中CA信号传导的物理控制机制的组成部分。我们发现 Tric-A的羧基尾域与RYR2通道相互作用，以直接调节CA释放 Sr。 Tric-a - / - 小鼠会出现心律不齐，严重的心脏肥大和纤维化 异丙肾上腺素治疗或横向主动脉收缩（TAC）手术。孤立的三ic-a - / - 心肌型细胞显示线粒体功能障碍，可能反映了SR CA超载引起的 线粒体在应力条件下的毒性。由于不受控制的CA发行已与 心脏病理学中的线粒体功能障碍，我们假设“与RYR2的三位一体相互作用 调节SR CA释放并与线粒体串扰。缺少三分流导致CA超负荷 内部SR并引起应力引起的CA毒性对线粒体。 SR线粒体失调 串扰有助于心力衰竭的发展”。我们进一步提出，针对三分线 介导的SR-Jochondria串扰代表了一种新型心血管治疗的方法 疾病。我们在该项目中设计的实验包含两个具体目的：目标1-定义 Tric-A/B和RYR2之间的功能相互作用在调节SR的CA信号传导中 在生理和病理条件下心肌细胞中的线粒体；目标2-阐明 Tric-A在介导应力诱导的心脏功能变化中的体内作用。