Mechanisms Underlying Mitrochondrial Dysfunction in the Diabetic Heart

描述（申请人提供）：线粒体网络作为氧化应激的来源和受害者，在许多重要疾病的起源中起着主导作用，其中糖尿病和肥胖患者的心肌病是最相关的疾病之一。我们的长期目标是确定在常见疾病（如糖尿病、肥胖和心力衰竭）中线粒体来源的活性氧（ROS）和氮（RNS）物种产生的关键机制步骤。在线粒体作为ROS和RNS发挥关键生理作用的关键信号细胞器的新兴观点中，我们的目标是实现对其在糖尿病相关代谢，收缩和电功能障碍（病理）生理学中的作用的更全面和定量的理解。目前提出的主要假设是：1)糖尿病动物心肌细胞更容易发生高血糖时氧化/亚硝化应激引起的线粒体功能障碍；2)糖尿病心脏代谢状态受损，更容易发生传导障碍、心律失常和收缩功能障碍。我们的假设基于以下观察结果：1)心肌细胞的线粒体网络对环境扰动极其敏感，一旦达到ROS的阈值水平，就会导致全细胞范围内线粒体膜电位的崩溃(?？M)和肌细胞不兴奋性；2) ROS和RNS的生物利用度通过共同的机制调控；的振荡m可以很容易地被外源性或内源性ROS清除剂或一氧化氮产生抑制剂阻止；4)线粒体能量的振荡驱动表面KATP电流和动作电位的振荡，影响完整心脏缺血后心律失常和收缩功能障碍的发生率。公共卫生相关性：糖尿病是由胰岛素分泌或作用不足引起的，影响全球1.5亿人，占美国人口的近6%。世界卫生组织最近的一项研究估计，到2030年，这些数字将增长到3.66亿。实现本研究的目标将有助于更好地了解线粒体功能障碍如何影响糖尿病患者心脏并发症的发生率和严重程度，并将确定针对这种常见疾病的治疗策略的新靶点。

DESCRIPTION (provided by applicant): The mitochondrial network, as a source and victim of oxidative stress has become a dominant player at the origin of many important diseases, among which cardiomyopathy in diabetic and obese patients ranks as one of the most relevant. Our long-term goal is to identify the critical mechanistic steps involved in the production of mitochondrially-derived reactive oxygen (ROS) and nitrogen (RNS) species in common diseases, such as diabetes, obesity, and heart failure. In the emerging view of the mitochondrion as a key signaling organelle in which ROS and RNS fulfill critical physiological roles, we aim to achieve a more comprehensive and quantitative understanding of its role in the (patho)physiology of diabetes related metabolic, contractile, and electrical dysfunction. The main hypotheses of the current proposal are that: 1) Cardiac myocytes from diabetic animals are more susceptible to mitochondrial dysfunction caused by oxidative/nitrosative stress in response to hyperglycemia, and 2) the diabetic heart is more susceptible to the incidence of conduction disturbances, arrhythmias and contractile dysfunction because of its compromised metabolic status. We base our hypotheses on the following observations: 1) the mitochondrial network of a cardiomyocyte is extremely sensitive to environmental perturbations once a threshold level of ROS is attained, leading to a cell-wide collapse of the mitochondrial membrane potential (??m) and myocyte inexcitability; 2) ROS and RNS bioavailability are regulated through common mechanisms; 3) oscillations of ??m can be readily prevented by exogenous or endogenous ROS scavengers, or nitric oxide production inhibitors; 4) oscillations of mitochondrial energetics drive oscillations of surface KATP current and action potentials, affecting the incidence of post-ischemic arrhythmias and contractile dysfunction in the intact heart. PUBLIC HEALTH RELEVANCE: Diabetes is caused by a deficiency in the secretion or action of insulin, affecting >150 million individuals worldwide and nearly 6% of the US population. A recent study by the World Health Organization estimates that those numbers will grow to 366 million by 2030. Achieving the aims of the present study will lead to a better understanding of how mitochondrial dysfunction affects the incidence and severity of cardiac complications among diabetics, and will identify novel targets for therapeutic strategies against this common disease.