THE ROLE OF COMPLEX 1 IN MITOCHONDRIAL DYSFUNCTION & FREE RADICAL PROD IN TYPE 1

复合物 1 在线粒体功能障碍中的作用

• 批准号: 8167975
• 负责人: Kenneth M Humphries
• 金额: $ 7.31万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167975
• 关键词: Address; Affect; Birth; Cardiac; Citric Acid Cycle; Complex; Computer Retrieval of Information on Scientific Projects Database; Defect; Diabetes Mellitus; Diabetic mouse; Disease; Disease Progression; Electron Transport; Event; Fatty Acids; Free Radicals; Funding; Future; Glucose; Goals; Grant; Heart; Heart Diseases; Heart Mitochondria; Heart failure; Impairment; Institution; Insulin-Dependent Diabetes Mellitus; Intervention; Metabolic Pathway; Mitochondria; Molecular; Morbidity - disease rate; Mus; Organelles; Oxidative Stress; Process; Production; Pyruvate; Pyruvates; Research; Research Personnel; Resources; Role; Source; Staging; Time; Tissues; United States National Institutes of Health; antioxidant therapy; base; diabetic; diabetic cardiomyopathy; improved; insight; mitochondrial dysfunction; mortality; prevent; therapeutic target

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Role of Complex I in Mitochondrial Dysfunction and Free Radical Production in Type 1 Diabetes. A leading cause of morbidity and mortality induced by diabetes is heart failure. Diabetes leads to a specific form of heart disease, termed diabetic cardiomyopathy, the causes of which are not completely understood. However, it is known that there are deficiencies in the processes that produce energy for cardiac tissue. These processes occur in distinct subcellular organelles called mitochondria. Loss of mitochondrial function leads to an increase in free radical production, which in turn generates an oxidative stres. The underlying mechanisms of mitochondrial dysfunction, and the role of free radicals in perpetuating diabetic cardiomyopathy are not well understood. The goal of the present project is to assess how mitochondrial function changes as a progression of type 1 diabetes using a genetically modified mouse that develops the disease at birth. Heart mitochondria from two-month-old mice (control and diabetic) are currently being evaluated. While this project is in early stages, the results are quite clear. Specifically, we have found that diabetic mice show no overt decrease in electron transport chain activity (which underlies the fundamental mechanism by which mitochondria produce energy). Furthermore, there is not a diabetes-induced increase in mitochondrial free radical production at this time point. Nevertheless, we have found clear differences in diabetic mitochondria as compared to controls. Specifically, mitochondria from diabetic mice have staggering limitations in the fuel sources they are able to utilize for energy production. They will only produce energy effectively using fatty acids, and have severe deficits in the ability to utilize pyruvate (an end product of glucose breakdown). Provocatively, the diabetic mitochondria also have severe deficits in the ability to produce energy using Krebs cycle intermediates (a central metabolic pathway carried out in the mitochondria). The significance of these findings will become clearer as the study progresses, but indicate significant impairments from an early stage. We anticipate future results of this study to provide important information regarding the molecular basis of the disease progression of type 1 diabetes. Specifically, this study will define the molecular aspects of mitochondrial energy production that are affected by the disease. In turn, this information will be used to determine the cause of increased free radical production and oxidative stress. This will address very fundamental questions. Specifically, how does mitochondrial dysfunction contribute to diabetic cardiomyopathy? Is mitochondrial dysfunction in the heart an early event in the progression of the disease? And, importantly, how can these defects be prevented? Results of this study will provide information about possible therapeutic targets to minimize the onset of diabetic cardiomyopathy and provide insight into improving pharmacological intervention using antioxidant therapy.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 复合物I在1型糖尿病中的线粒体功能障碍和自由基产生中的作用。 糖尿病引起的发病和死亡率的主要原因是心力衰竭。 糖尿病导致一种特定的心脏病形式，称为糖尿病心肌病，其原因尚未完全理解。 然而，众所周知，在过程中存在缺乏，可以为心脏组织产生能量。 这些过程发生在不同的亚细胞细胞器中，称为线粒体。 线粒体功能的丧失会导致自由基产生的增加，这又产生了氧化条。线粒体功能障碍的基本机制以及自由基在永久性糖尿病心肌病中的作用尚不清楚。 本项目的目的是评估线粒体功能如何使用遗传改良的小鼠出生时发展为1型糖尿病的进展。 目前正在评估来自两个月大的小鼠（对照和糖尿病）的心脏线粒体。 虽然该项目处于早期阶段，但结果非常清楚。 具体而言，我们发现糖尿病小鼠没有明显降低电子传输链活性（这是线粒体产生能量的基本机制的基础）。 此外，目前，线粒体自由基产生的增加没有糖尿病诱导的增加。 然而，与对照组相比，我们发现糖尿病线粒体上有明显的差异。 具体而言，来自糖尿病小鼠的线粒体在能够用于能源生产的燃料来源中具有惊人的局限性。 它们只会使用脂肪酸有效产生能量，并且在利用丙酮酸的能力（葡萄糖崩溃的最终产物）中存在严重的缺陷。 挑衅地，糖尿病线粒体在使用克雷布斯循环中间体（线粒体中进行的中央代谢途径）产生能量的能力上也有严重的缺陷。 随着研究的进行，这些发现的重要性将变得更加清晰，但表明早期阶段的重大损害。 我们预计这项研究的未来结果将提供有关1型糖尿病疾病进展的分子基础的重要信息。 具体而言，这项研究将定义受疾病影响的线粒体能量产生的分子方面。 反过来，此信息将用于确定自由基生产增加和氧化应激增加的原因。这将解决非常基本的问题。 具体而言，线粒体功能障碍如何导致糖尿病心肌病？ 心脏的线粒体功能障碍是疾病进展的早期事件吗？ 而且，重要的是，如何防止这些缺陷？ 这项研究的结果将提供有关可能的治疗靶标的信息，以最大程度地减少糖尿病心肌病的发作，并提供对使用抗氧化剂治疗改善药理学干预的见解。