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

基本信息

批准号：
8341677
负责人：
Wang Wang
金额：
$ 44.18万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/8341677
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: This project investigates the mechanistic coupling of mitochondrial respiration and bursting superoxide production. Our goal is to establish that decreased superoxide flash activity is a novel and early biomarker for mitochondrial dysfunction, which leads to oxidative stress in heart failure.

描述（由申请人提供）：健康和衰竭心脏中的线粒体呼吸和超氧化物产生。在心肌细胞中，线粒体在氧化代谢、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) 活动驱动 ATP 合成和活性氧 (ROS) 生成。在衰竭的心脏中，线粒体呼吸经常受到损害，导致 ATP 产生减少，并且矛盾的是，氧化应激增加。因此，确定健康心脏中线粒体呼吸和 ROS 产生如何受到调节以及它们如何导致衰竭心脏中的氧化应激是非常有意义的。最近，我们在心肌细胞和心肌的单个线粒体中发现了短暂的超氧化物产生事件，称为超氧化物闪现。初步数据表明，超氧化物闪光需要完整的 ETC 活性，并且其频率会因生理或病理治疗而改变。我们假设超氧化物闪蒸与单个线粒体中 ETC 活性的随机加速相关，并受到线粒体生物能学关键调节因子的调节，包括 Ca2+、通透性转换孔 (PTP) 和裂变/融合。如果这个假设成立，超氧化物闪光可能会起作用作为单个线粒体呼吸和 ROS 产生的综合指数。此外，超氧化物闪光成像可能有助于确定线粒体或细胞质 ROS 是否导致衰竭心脏中的氧化应激。我们提出以下具体目标，以确定线粒体呼吸和超氧化物闪速产生的机制耦合及其在心力衰竭氧化应激中的作用：目标 1：检验超氧化物闪速由线粒体呼吸瞬时加速引起并受线粒体调节的假设Ca2+、PTP 和裂变/聚变动力学。目标 2：检验病理应激在心力衰竭早期和检测线粒体功能障碍的明显迹象之前抑制超氧化物闪现活性的假设。目标 3：确定线粒体或胞质 ROS 的增加是否会导致线粒体呼吸功能障碍期间的氧化应激。公共健康相关性：该项目研究线粒体呼吸和超氧化物产生爆发的机械耦合。我们的目标是确定超氧化物闪现活性降低是线粒体功能障碍的一种新型早期生物标志物，线粒体功能障碍会导致心力衰竭的氧化应激。