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）：由于血液供应减少心脏而引起的并发症是全球死亡和衰弱的主要原因。然而，恢复冠状动脉血液流向看似可行的心肌组织，通常伴随着心脏功能的丧失，并且从长远来看是心力衰竭的发展。这种矛盾的现象广泛称为缺血/再灌注损伤，在老年人中表现得更严重。线粒体可能在心肌缺血/再灌注损伤中起核心作用。维持心脏能量状况和功能至关重要，线粒体在缺血期间的呼吸和氧化磷酸化速率下降，在再灌注时会进一步依赖年龄的缺陷。拟议的研究旨在通过统一与缺血/再灌注有关的两个事件来定义功能损失的机制：Ca2+过载和促氧化剂的产生。心脏缺血导致细胞色素C与内部线粒体膜的脱离，这一事件导致电子传输速率下降。在再灌注过程中，氧化还原敏感的酶复合物I，酮戊二酸脱氢酶和刺刺酶的活性下降。分离的线粒体暴露于模仿从缺血到再灌注过渡的pH和Ca2+浓度的改变会导致细胞色素C分解和对这些氧化还原敏感酶的氧化抑制。根据氧化应激的幅度和持续时间，可逆抑制可以发展为不可逆的失活。假设：在心肌缺血/再灌注过程中线粒体Ca2+浓度的增加导致细胞色素C与内部线粒体内部膜的解离，从而导致自由基生产的增加和氧化抑制氧化剂的氧化敏感酶。这会瞬时降低线粒体呼吸，自由基产生的速度以及对不可逆转的氧化损伤的敏感性。老化增加了线粒体Ca2+过载，从而增加了从可逆调制到线粒体功能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会改变心脏缺血和再灌注的持续时间，以确定分子事件，从而导致线粒体促氧化剂的产生增加（AIM 1），特定的目标和机制，依赖氧化还原的损失（AIM 2），生物化学损失（AIM 2），以及AIR 2），AIL 2），AIL 2） - AIL 2） - AIL 2） - AIL 2）心脏缺血/再灌注期间的线粒体功能（目标1和2）。需要阐明负责缺血/再灌注损伤的分子事件，以优化有利影响结果的策略，尤其是在老年人群中。外行描述：心脏病是衰弱和死亡的主要原因，尤其是在老龄化人群中。我们的研究试图定义与年龄相关的因素，以增强心脏病的严重性，以设计改善结果的策略。