Mitochondrial Respiration and Superoxide Production in Healthy and Failing Heart

健康和衰竭心脏中的线粒体呼吸和超氧化物产生

• 批准号: 8520390
• 负责人: Wang Wang
• 金额: $ 40.51万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8520390
• 关键词: ATP Synthesis Pathway; Acceleration; Antioxidants; Bioenergetics; Biological Markers; Cardiac Myocytes; Cardiovascular Diseases; Catecholamines; Cell Fate Control; Cell Respiration; Cells; Chronic; Complex; Coupled; Coupling; DNA; Data; Detection; Development; Electron Transport; Electrons; Evaluation; Event; Exposure to; Frequencies; Functional disorder; Generations; Genes; Goals; Heart; Heart Rate; Heart failure; Homeostasis; Hydrogen Peroxide; Image; In Situ; In Vitro; Individual; Ions; Ischemia; Membrane Potentials; Methods; Mitochondria; Modeling; Monitor; Muscle Cells; Myocardium; Names; Oxidation-Reduction; Oxidative Stress; Permeability; Physiological; Play; Population; Production; Proteins; Reactive Oxygen Species; Relative (related person); Reperfusion Therapy; Resolution; Respiration; Respiratory Chain; Role; SOD2 gene; Signal Transduction; Site; Source; Staging; Stress; Superoxides; Techniques; Testing; Time; Tissues; Transgenic Mice; Transgenic Organisms; indexing; interest; mitochondrial dysfunction; mitochondrial membrane; novel; overexpression; oxidation; pressure; respiratory; uptake

DESCRIPTION (provided by applicant): Mitochondrial Respiration and Superoxide Production in Healthy and Failing Heart. In cardiac myocytes, mitochondrion plays multi-functional roles in oxidative metabolism, ion homeostasis, signal transduction, and cell fate regulation. Mitochondrial respiration through the electron transport chain (ETC) activity drives ATP synthesis and reactive oxygen species (ROS) generation. In the failing heart, mitochondrial respiration is often compromised, resulting in decreased ATP production and, paradoxically, increased oxidative stress. It is therefore of great interest to determine how mitochondrial respiration and ROS production are regulated in the healthy heart and how they contribute to oxidative stress in the failing heart. Recently, we discovered a transient superoxide production event, named superoxide flash, in individual mitochondria of cardiac myocytes and the myocardium. Preliminary data indicate that the superoxide flash requires intact ETC activity, and its frequency is altered by physiological or pathological treatments. We hypothesize that the superoxide flash is coupled to stochastic acceleration of ETC activity in single mitochondria and modulated by key regulators of mitochondrial bioenergetics, including Ca2+, permeability transition pore (PTP), and fission/fusion. If this hypothesis is true, superoxide flashes may serve as a composite index of single mitochondrion respiration and ROS production. Further, imaging superoxide flashes may help determine whether mitochondrial or cytosolic ROS is responsible for oxidative stress in the failing heart. We propose the following specific aims to determine the mechanistic coupling of mitochondrial respiration and superoxide flash production and their role in oxidative stress in heart failure: Aim 1: To test the hypothesis that superoxide flash arises from transient acceleration of mitochondrial respiration and is modulated by mitochondrial Ca2+, PTP and fission/fusion dynamics. Aim 2: To test the hypothesis that pathological stress inhibits superoxide flash activity at an early stage of heart failure and prior to detection of overt signs f mitochondrial dysfunction. Aim 3: To determine whether increased mitochondrial or cytosolic ROS contributes to oxidative stress during mitochondrial respiratory dysfunction.

描述（由申请人提供）：健康和衰竭心脏的线粒体呼吸和超氧化物产生。在心肌细胞中，钙离子在氧化代谢、离子稳态、信号转导和细胞命运调节中发挥多功能作用。线粒体呼吸通过电子传递链（ETC）活性驱动ATP合成和活性氧（ROS）产生。在衰竭的心脏中，线粒体呼吸通常受到损害，导致ATP产生减少，矛盾的是，氧化应激增加。因此，确定健康心脏中线粒体呼吸和ROS产生如何调节以及它们如何促进衰竭心脏中的氧化应激是非常有趣的。最近，我们发现了一个短暂的超氧化物产生事件，称为超氧化物闪光，在个别线粒体的心肌细胞和心肌。初步数据表明，超氧化物闪光需要完整的ETC活动，其频率被改变的生理或病理治疗。我们假设，超氧化物闪光耦合到随机加速ETC活动在单个线粒体和线粒体生物能量学的关键调节器，包括Ca 2+，渗透性转换孔（PTP），和裂变/融合调制。如果这一假设是正确的，超氧化物闪光可能有助于 作为单细胞呼吸和活性氧产生的综合指标。此外，超氧化物闪光成像可能有助于确定线粒体或胞质ROS是否是衰竭心脏中氧化应激的原因。我们提出了以下具体目标，以确定线粒体呼吸和超氧化物闪光的生产及其在氧化应激在心力衰竭中的作用的机械耦合：目的1：为了测试的假设，超氧化物闪光来自线粒体呼吸的瞬时加速和线粒体Ca 2+，PTP和裂变/融合动力学调制。目标二：检验病理性应激在心力衰竭早期和检测到线粒体功能障碍明显体征之前抑制超氧化物闪光活性的假设。目的3：确定是否增加线粒体或胞质ROS有助于线粒体呼吸功能障碍期间的氧化应激。