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Modulation of Mitochondrial Function by Pro-Oxidants

促氧化剂对线粒体功能的调节

基本信息

批准号：
7897640
负责人：
LUKE I. SZWEDA
金额：
$ 32.42万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-01-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7897640
关键词：
Accounting Aconitate Hydratase Age Aging Animals Antioxidants Biochemical Bioenergetics Blood flow Cardiac Cardiolipins Cause of Death Cessation of life Chemicals Citric Acid Cycle Coronary Data Development Dissociation Elderly Electron Transport Electrons Enzymes Equilibrium Event Excision Exhibits Free Radicals Functional disorder Heart Heart Diseases Heart failure Homeostasis Hydrogen Peroxide In Vitro Inner mitochondrial membrane Ischemia Lead Link Maintenance Measurement Membrane Mitochondria Modeling Modification Molecular Multienzyme Complexes Myocardial Myocardial Ischemia Myocardial Reperfusion Myocardial tissue Outcome Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Play Population Predisposition Production Proteins Publishing Rattus Reactive Oxygen Species Relative (related person)Reperfusion Injury Reperfusion Therapy Respiration Respiratory physiology Role Severities Superoxides Testing Variant Vascular blood supply age related aged aging population base cytochrome c design enhancing factor functional decline improved in vivo ketoglutarate dehydrogenase mature animal mitochondrial dysfunction oxidative damage peroxidation protein function research study respiratory response restoration uptake

项目摘要

DESCRIPTION (provided by applicant): Complications arising from reduction of blood supply to the heart are a leading cause of death and debilitation worldwide. Nevertheless, restoration of coronary blood flow to seemingly viable myocardial tissue is often accompanied by loss of cardiac function and, in the long term, development of heart failure. This paradoxical phenomenon, broadly termed ischemia/reperfusion injury, is manifested more severely in the elderly. Mitochondria likely play a central role in myocardial ischemia/reperfusion injury. Critical for the maintenance of cardiac energy status and function, mitochondria exhibit declines in the rate of respiration and oxidative phosphorylation during ischemia, with further age-dependent deficits evident upon reperfusion. The proposed studies seek to define mechanisms responsible for this loss in function by unifying two events associated with ischemia/reperfusion: Ca2+ overload and pro-oxidant production. Cardiac ischemia results in detachment of cytochrome c from the inner mitochondrial membrane, an event responsible for declines in the rate of electron transport. During reperfusion, the redox sensitive enzymes complex I, a-ketoglutarate dehydrogenase, and aconitase exhibit declines in activity. Exposure of isolated mitochondria to alterations in pH and Ca2+ concentration that mimic the transition from ischemia to reperfusion results in cytochrome c dissociation and oxidative inhibition of these redox sensitive enzymes. Depending on the magnitude and duration of oxidative stress, reversible inhibition can progress to irreversible inactivation. It is hypothesized that: Increases in mitochondrial Ca2+ concentration during myocardial ischemia/reperfusion lead to dissociation of cytochrome c from the inner mitochondrial membrane resulting in an increase in free radical production and oxidative inhibition of redox sensitive enzymes. This transiently reduces the rates of mitochondrial respiration, free radical production, and susceptibility to irreversible oxidative damage. Aging augments mitochondrial Ca2+ overload, increasing the likelihood of progression from reversible modulation to irreversible inactivation of mitochondrial function. Utilizing an in vivo rat model, durations of cardiac ischemia and reperfusion will be varied using animals of different ages to identify molecular events that result in increased mitochondrial pro-oxidant production (Aim 1), specific targets and mechanisms of redox- dependent modification (Aim 2), biochemical consequences of oxidative modification (Aim 2), and age- dependent factors that promote irreparable loss in mitochondrial function during cardiac ischemia/reperfusion (Aims 1 and 2). Elucidation of molecular events responsible for ischemia/reperfusion injury is required for optimization of strategies for favorably influencing the outcome particularly in the elderly population. Lay Description: Heart disease is a leading cause of debilitation and death, particularly in the aging population. Our studies seek to define age-related factors that enhance the severity of heart disease in an effort to design strategies to improve the outcome.

描述（由申请人提供）：心脏供血减少引起的并发症是全世界死亡和衰弱的主要原因。然而，冠状动脉血流恢复到看似存活的心肌组织常常伴随着心脏功能的丧失，并且从长远来看，会导致心力衰竭的发展。这种矛盾的现象被广泛地称为缺血/再灌注损伤，在老年人中表现得更为严重。线粒体可能在心肌缺血/再灌注损伤中发挥核心作用。对于维持心脏能量状态和功能至关重要，线粒体在缺血期间表现出呼吸速率和氧化磷酸化的下降，并且在再灌注时进一步出现明显的年龄依赖性缺陷。拟议的研究试图通过统一与缺血/再灌注相关的两个事件来定义导致这种功能丧失的机制：Ca2+超载和促氧化剂的产生。心脏缺血导致细胞色素 c 从线粒体内膜脱离，这是导致电子传递速率下降的原因。再灌注期间，氧化还原敏感酶复合物 I、α-酮戊二酸脱氢酶和乌头酸酶表现出活性下降。将分离的线粒体暴露于 pH 和 Ca2+ 浓度的变化（模拟从缺血到再灌注的转变）会导致细胞色素 c 解离和这些氧化还原敏感酶的氧化抑制。根据氧化应激的程度和持续时间，可逆抑制可能进展为不可逆失活。假设：心肌缺血/再灌注期间线粒体 Ca2+ 浓度增加导致细胞色素 c 从线粒体内膜解离，从而导致自由基产生增加和氧化还原敏感酶的氧化抑制。这会暂时降低线粒体呼吸速率、自由基产生以及对不可逆氧化损伤的敏感性。衰老会增加线粒体 Ca2+ 超载，增加线粒体功能从可逆调节发展为不可逆失活的可能性。利用体内大鼠模型，使用不同年龄的动物，心脏缺血和再灌注的持续时间会有所不同，以确定导致线粒体促氧化剂产生增加的分子事件（目标 1）、氧化还原依赖性修饰的具体目标和机制（目标 2）、氧化修饰的生化后果（目标 2）以及促进线粒体促氧化剂不可挽回损失的年龄依赖性因素。心脏缺血/再灌注期间的线粒体功能（目标 1 和 2）。需要阐明导致缺血/再灌注损伤的分子事件，以优化有利影响结果的策略，特别是在老年人群中。外行描述：心脏病是导致虚弱和死亡的主要原因，特别是在老龄化人口中。我们的研究旨在确定导致心脏病严重程度的与年龄相关的因素，以设计改善结果的策略。