Structural-functional zoning of the mitochondrion in cardiac Ca2+, ROS, and energetics regulation

线粒体在心脏 Ca2 、ROS 和能量调节中的结构功能分区

基本信息

批准号：
9913581
负责人：
GYORGY CSORDAS
金额：
$ 61.26万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
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/9913581
关键词：
Area Biogenesis Cardiac Cardiac Myocytes Carrier Proteins Cell Death Complex Consumption Coupling Crista ampullaris Data Defense Mechanisms Diffusion Disease Distal Dynamin Electron Transport Energy Metabolism Ensure Environment Equilibrium Etiology Functional disorder Futile Cycling Generations Heart Heart failure Impairment Inner mitochondrial membrane Knowledge Lead Literature Maintenance Mediating Membrane Mitochondria Mitochondrial DNA Mitochondrial Matrix Muscle Cells Muscle Contraction Optic Atrophy Oxidative Stress Permeability Physiological Production Proteins Publishing Quality Control Reactive Oxygen Species Regulation Risk Sarcoplasmic Reticulum Signal Transduction Stress Structure Testing Text Toxic effect Transmission Electron Microscopy Tubular formation base cardiogenesis electron tomography energy balance heart metabolism high risk microscopic imaging protein distribution repaired therapeutic target uptake

项目摘要

Mitochondrial impairment is a main contributor and potential therapeutic target in the development of heart failure (HF). During excitation-contraction coupling, Ca2+ is released from the sarcoplasmic reticulum of dyadic junction (jSR) to initiate muscle contraction. jSR is often tethered to mitochondria, where a high [Ca2+] nanodomain is created to facilitate Ca2+ propagation to the mitochondrial matrix to stimulate ATP production (excitation-energetics coupling). The beating heart consumes much energy; thus, cardiomyocytes must be efficient in dynamically balancing energy demands and supplies while avoiding potential Ca2+ mediated toxicity. We find that mitochondrial Ca2+ uniporter (mtCU), responsible for Ca2+ uptake, concentrate to hotspots at the interface with jSR whereas the robust Na+-dependent Ca2+ extrusion (mitochondrial Na+/Ca2+ exchanger, NCLX) is mostly excluded from these segments. In this proposal, we put forward the overarching theme that the mitochondria, which associate with jSR, remodel their membrane structure and protein distribution asymmetrically into two zones proximal and distal from jSR, to protect their long-term integrity while serving the excitation-energetics coupling. Imbalance in this adaptation leads to HF. Based on our preliminary data and published literature; we hypothesize that mitochondrial Ca2+ influx and efflux are uniquely distanced, and so a [Ca2+] gradient is created in the matrix to ensure an effective Ca2+ mediated energy production without toxicity by minimizing the amount of Ca2+ required to cycle through the matrix for a given [Ca2+] rise. The mitochondrial zone proximal to the jSR forms a Ca2+ receptacle with enhanced Ca2+ entry but limited exit and less membrane barriers for diffusion, while the mitochondrial zone distal to jSR has dense cristae membrane for vigorous ATP generation without subjecting to Ca2+ toxicity. Finally, the constant high Ca2+ in Ca2+ receptacle zone renders it more susceptible for physiological mitophagy via mitochondrial fission. However, prolonged stress turns this physiological defense mechanism maladaptive, with excess of fragmented mitochondria without jSR Ca2+ input (no excitation-energetics coupling) due to the loss of juxtaposition, as such leads to HF etiology. Three specific aims are: 1) Investigate the physiological implications of differential submitochondrial distribution of mitochondrial Ca2+ uptake and extrusion mechanisms in excitation-energetics coupling. 2. To establish submitochondrial structural zoning associated with the zonal Ca2+ transport. 3. To assess the impact of zoning on mitochondrial maintenance/quality control and how excessive fragmentations associated with stresses could turn zoning maladaptive and lead to HF.

线粒体损伤是主要贡献者和潜在的治疗靶点心力衰竭的发展（HF）。在激发反应耦合期间，Ca2+从二元连接（JSR）的肌质网启动肌肉收缩。 JSR经常束缚在线粒体上，在该线粒体上创建高[Ca2+]纳米域以促进Ca2+ 向线粒体基质传播以刺激ATP的产生（激发能源耦合）。跳动的心消耗大量精力。因此，心肌细胞必须有效动态平衡能量的需求和供应，同时避免潜在的Ca2+介导毒性。我们发现线粒体Ca2+ Uniporter（MTCU）负责Ca2+摄取，集中在与JSR界面处的热点，而稳健的Na+依赖性CA2+ 挤出（线粒体Na+/Ca2+交换器，NCLX）大多被排除在这些段之外。在此提案中，我们提出了一个总体主题，即线粒体，使用JSR，将其膜结构和蛋白质分布不对称地重塑为两个 JSR的近端和远端区域，以保护其长期完整性，同时为激发 - 能源耦合。这种适应的不平衡导致HF。基于我们初步数据和文献；我们假设线粒体Ca2+流入和外排是独特的，因此在矩阵中创建了[Ca2+]梯度，以确保有效的Ca2+介导的能源产生而无毒性，通过最大程度地减少Ca2+的量需要在给定的[Ca2+]上升的矩阵中循环循环。线粒体区域 JSR形成一个Ca2+插座，具有增强的Ca2+进入但出口有限，膜较少扩散的障碍物，而线粒体区域远端的JSR远端具有致密的Cristae膜剧烈的ATP生成而无需CA2+毒性。最后，恒定的高Ca2+ in CA2+插座区使它更容易通过线粒体生理线粒体裂变。但是，长期压力使这种生理防御机制不良适应，没有JSR CA2+输入的线粒体碎片过多（无激发能源耦合）由于并置的丧失，因此导致了HF病因。三个具体目标是： 1）调查差异提交的生理含义激发 - 能源耦合中的线粒体Ca2+摄取和挤出机制。 2 建立与区域Ca2+传输相关的提交方案结构分区。 3 评估分区对线粒体维护/质量控制的影响以及如何过度与应力相关的碎片可能会变成适应不良的分区并导致HF。