FUNDC1 and diabetic cardiomyopathy

项目摘要 线粒体对能量生产是必不可少的，但如果受损，它们就会成为 活性氧物种和促细胞凋亡因子。越来越多的证据表明线粒体 功能障碍是糖尿病心肌病发生发展的中心事件。然而，分子 糖尿病引起心肌细胞线粒体功能障碍的机制仍然存在 特征不佳的。我们在这份申请中包含的令人兴奋的初步数据表明， FUN14结构域包含1(Fund1)蛋白，是一种线粒体外膜蛋白 在糖尿病心脏中大量增加，导致线粒体功能障碍和糖尿病心肌病。 在机制上，糖尿病患者Fundc1的异常表达增加了内质网(ER)- 线粒体接触，促进钙离子从内质网转移到线粒体，从而导致 线粒体钙超载、心肌细胞死亡和心功能不全。心脏特异型 Fundc1基因缺失减少了内质网-线粒体的接触，减轻了I型和 II型糖尿病小鼠。因此，这一提议的中心假设是异常的Fundc1 糖尿病患者的表达通过以下途径损害线粒体功能而导致心肌病 内质网-线粒体接触增强。这一假设将通过使用得失来检验 在动物模型和培养的心肌细胞中的功能和药物/遗传策略。 目的1确定Fundc1表达增加在骨肉瘤发生发展中的重要作用。 糖尿病心肌病。在这个目标中，我们将测试增强的Fundc1表达的假设 通过损害线粒体功能而导致心脏结构损伤和功能障碍 糖尿病。目的2阐明糖尿病患者Fundc1表达上调的机制 线粒体功能，导致心肌病。在这个目标中，我们将检验假设 糖尿病增强的Fundc1表达通过促进ER-1而损害线粒体功能 线粒体接触。我们将确定Fundc1是否介导糖尿病患者的内质网-线粒体接触 心脏，研究FundC1增加是否导致线粒体功能障碍和心肌细胞 通过增加钙离子从内质网向线粒体的转移而死亡，并检测是否减少内质网- 利用IP3R2改善糖尿病大鼠心肌线粒体和心功能 心肌细胞特异性基因敲除小鼠。这项极具创新性的提案的完成将有助于 开发治疗糖尿病心肌病的新范例。

Project Summary Mitochondria are essential for energy production, but, if damaged, they become a major source of reactive oxygen species and proapoptotic factors. Increasing evidence suggests that mitochondrial dysfunction is a central event in the development of diabetic cardiomyopathy. However, the molecular mechanisms responsible for diabetes-caused mitochondrial dysfunction in cadiomyocytes remain poorly characterized. Our exciting preliminary data included in this application show that the levels of the FUN14 domain containing 1 (FUNDC1) protein, a mitochondrial outer-membrane protein, are highly increased in diabetic hearts resulting in mitochondrial dysfunction and diabetic cardiomyopathy. Mechanistically, aberrant FUNDC1 expression in diabetes increases endoplamsmic reticulum (ER)- mitochondria contact, which promotes Ca2+ transfer from the ER to the mitochondria and thus results in mitochondrial Ca2+ overload, cardiomyocyte death, and cardiac dysfunction. Cardiac-specific deletion of FUNDC1 reduces ER-mitochondria contacts, attenuating cardiac dysfunction in Type I and Type II diabetic mice. Thus, the central hypothesis of this proposal is that aberrant FUNDC1 expression in diabetes leads to cardiomyopathy by impairing mitochondrial function through enhancement of ER-mitochondria contacts. This hypothesis will be tested by using gain-/loss-of function and pharmacologic/genetic strategies in both animal models and cultured cardiomyocytes. Aim 1 is to establish the essential roles of increased FUNDC1 expression in the development of diabetic cardiomyopathy. In this Aim, we will test the hypotheis that enhanced FUNDC1 expression causes cardiac structural damage and dysfunction by compromising mitochondrial function in diabetes. Aim 2 is to elucidate the mechanism by which FUNDC1 upregulation in diabetes impairs mitochondrial function, leading to cardiomyopathy. In this aim, we will test the hypothesis that diabetes-enhanced FUNDC1 expression impairs mitochondrial function by promoting the ER- mitochondria contacts. We will determine if FUNDC1 mediates ER-mitochondria contacts in diabetic hearts, investigate whether increased FUNDC1 causes mitochondrial dysfunction and cardiomyocyte death by increasing Ca2+ transfer from ER to mitochondria, and examine whether diminishing ER- mitochondrial Ca2+ flux improves mitochondrial and cardiac function in diabetic hearts using IP3R2 cardiomyocyte-specific knockout mice. The completion of this highly innovative proposal will help develop a new paradigm for treating diabetic cardiomyopathy.