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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：
9037700
负责人：
Wang Wang
金额：
$ 42.55万
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 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9037700
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 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.

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，线粒体在氧化代谢、离子稳态、信号转导和细胞命运调节等方面发挥着多种功能。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）的产生。在衰竭的心脏中，线粒体呼吸经常受损，导致ATP产生减少，矛盾的是，氧化应激增加。因此，确定线粒体呼吸和ROS的产生如何在健康心脏中受到调节以及它们如何在衰竭心脏中促进氧化应激是非常有趣的。最近，我们在心肌细胞和心肌的单个线粒体中发现了一种瞬时超氧化物产生事件，称为超氧化物闪变。初步数据表明，超氧化物闪光需要完整的ETC活性，其频率会因生理或病理处理而改变。我们假设，在单个线粒体中，超氧化物闪变与ETC活性的随机加速相耦合，并受到线粒体生物能量学的关键调节因子的调节，包括Ca2+、通透性过渡孔（PTP）和裂变/融合。如果这个假设是正确的，那么超氧化物闪光可能起作用