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

• 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
• 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

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.

线粒体损伤是该病的主要诱因和潜在的治疗靶点 心力衰竭（HF）的发展。在兴奋-收缩耦合过程中，Ca2+从 二元连接肌质网 (jSR) 启动肌肉收缩。 jSR 经常是 与线粒体相连，在线粒体中产生高 [Ca2+] 纳米域以促进 Ca2+ 传播到线粒体基质以刺激 ATP 产生（激发-能量 耦合）。心脏跳动消耗大量能量；因此，心肌细胞必须有效地 动态平衡能量需求和供应，同时避免潜在的 Ca2+ 介导 毒性。我们发现负责 Ca2+ 摄取的线粒体 Ca2+ 单向转运蛋白 (mtCU) 集中于与 jSR 界面处的热点，而强大的 Na+ 依赖性 Ca2+ 挤压（线粒体 Na+/Ca2+ 交换器，NCLX）大多被排除在这些片段之外。 在这项提案中，我们提出了总体主题，即线粒体，它与 使用 jSR，将其膜结构和蛋白质分布不对称地重塑为两个 jSR 近端和远端区域，以保护其长期完整性，同时服务于 激发-能量耦合。这种适应的不平衡会导致心力衰竭。基于我们的 初步数据和已发表的文献；我们假设线粒体 Ca2+ 流入 流出的距离是唯一的，因此在矩阵中创建 [Ca2+] 梯度以确保 通过最大限度地减少 Ca2+ 的量，有效地产生 Ca2+ 介导的能量，且无毒性 对于给定的 [Ca2+] 上升，需要循环遍历矩阵。线粒体近端区 jSR 形成 Ca2+ 容器，Ca2+ 进入增强，但退出有限且膜较少 扩散障碍，而 jSR 远端的线粒体区域具有致密的嵴膜， ATP 生成旺盛，且不受 Ca2+ 毒性影响。最后，恒定的高Ca2+ Ca2+ 受体区使其更容易通过线粒体进行生理线粒体自噬 裂变。然而，长期的压力会使这种生理防御机制适应不良， 具有过量的碎片线粒体，没有 jSR Ca2+ 输入（无激发能量 耦合）由于并置的丧失，因此导致 HF 病因。三个具体目标是： 1）研究不同亚软骨分布的生理学意义 激发-能量耦合中线粒体 Ca2+ 吸收和挤出机制。 2. 到 建立与带状 Ca2+ 运输相关的软骨下结构分区。 3. 到 评估分区对线粒体维护/质量控制的影响以及过度程度 与压力相关的碎片可能会导致分区适应不良并导致心力衰竭。