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

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 复合物I在1型糖尿病线粒体功能障碍和自由基产生中的作用。 糖尿病引起的发病率和死亡率的主要原因是心力衰竭。 糖尿病导致一种特殊形式的心脏病，称为糖尿病性心肌病，其原因尚不完全清楚。 然而，已知在为心脏组织产生能量的过程中存在缺陷。 这些过程发生在称为线粒体的不同亚细胞细胞器中。 线粒体功能的丧失导致自由基产生增加，这反过来又产生氧化应激。线粒体功能障碍的潜在机制，以及自由基在糖尿病心肌病中的作用尚不清楚。 本项目的目标是评估线粒体功能如何随着1型糖尿病的进展而变化，使用在出生时发展该疾病的转基因小鼠。 目前正在评估两个月大的小鼠（对照组和糖尿病组）的心脏线粒体。 虽然这个项目还处于早期阶段，但结果已经非常明显。 具体地说，我们发现糖尿病小鼠的电子传递链活性没有明显降低（这是线粒体产生能量的基本机制的基础）。 此外，在该时间点，线粒体自由基产生没有糖尿病诱导的增加。 然而，我们发现糖尿病线粒体与对照组相比存在明显差异。 具体来说，来自糖尿病小鼠的线粒体在它们能够用于能量生产的燃料来源方面具有惊人的限制。 它们只能有效地利用脂肪酸产生能量，并且在利用丙酮酸（葡萄糖分解的最终产物）的能力方面存在严重缺陷。 具有挑衅性的是，糖尿病线粒体在使用克雷布斯循环中间体（在线粒体中进行的中心代谢途径）产生能量的能力方面也具有严重缺陷。 随着研究的进展，这些发现的意义将变得更加清晰，但表明早期阶段存在显著的损害。 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。 具体来说，这项研究将确定线粒体能量产生的分子方面受到疾病的影响。 反过来，这些信息将用于确定增加的自由基产生和氧化应激的原因。这将解决非常根本的问题。 具体来说，线粒体功能障碍如何导致糖尿病心肌病？ 心脏线粒体功能障碍是疾病进展的早期事件吗？ 更重要的是，如何预防这些缺陷？ 本研究的结果将提供有关可能的治疗靶点的信息，以尽量减少糖尿病心肌病的发作，并提供洞察力，以改善药物干预使用抗氧化治疗。

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.