Mitochondrial Ca2+ Transport in Heart Cells

我们研究的长期目标是阐明线粒体钙离子转运的机制。 生理和病理条件下的心肌细胞。广泛的研究已经 提示线粒体Ca~(2+)在控制细胞内Ca~(2+)稳态、能量方面起着关键作用 新陈代谢和细胞凋亡。然而，人们对其分子同一性和功能多样性知之甚少。 线粒体钙离子转运体。我们的中心假说是“心肌线粒体至少包含两个 钙激活的内流机制，一种线粒体兰尼定受体，在 较低的钙离子范围(&lt；50^M)和在较高范围内运行最有效的钙离子转运体 Ca2+。这两种钙离子转运蛋白能够很好地隔离钙离子，并且在调节钙离子方面具有互补性。 动态平衡、三磷酸腺苷的产生和活性氧的产生。这些线粒体钙离子- 在生理上，中介功能是通过伴随线粒体ADP的增加而实现的，服务于 不仅可以作为ATP生产的底物，而且还可以作为线粒体通透性转换孔的抑制剂。在……里面 在疾病状态下，这种钙离子和ADP之间的协调相互作用被破坏，并容易使细胞 这四个具体目标是：1)进一步表征 线粒体Ryanodine受体的分子特性，2)评价线粒体的不同作用 Ryanodine受体和钙离子单一转运体在钙调节中的作用，3)确定线粒体的调制 氧化还原环境中钙的摄取，以及4)阐明线粒体钙和ADP在氧化还原环境中的作用。 在健康和心肌病心脏中平衡细胞ATP生成和钙稳态。劳作 与我们的合作者密切合作，我们将使用包括细胞生物学在内的多学科方法， 生物化学，生物物理学和分子生物学，以阐明分子和功能特征 线粒体钙离子内流机制。线粒体DNA引起的疾病的最新研究 突变或线粒体功能障碍都表明，钙离子的去调节是最关键的。一些例子 这些疾病中有慢性心力衰竭的心肌病、缺血性心脏病、神经退行性疾病 疾病、糖尿病、肥胖和衰老。因此，完成我们的研究目标不仅要有一个 对我们理解线粒体介导的病因学基本机制的重大影响 这不仅取决于我们为治疗这些疾病而制定的治疗手段，而且还在于我们的战略。

The long-term objective of our research is to elucidate mechanisms of mitochondrial Ca2+ transport in cardiac muscle cells under both physiological and pathological conditions. Extensive studies have implicated that mitochondrial Ca2+ play a pivotal role in controlling cellular Ca2+ homeostasis, energy metabolism, and apoptosis. However, little is known about the molecular identities and functional diversities of mitochondrial Ca2+ transporters. Our Central hypothesis is that "cardiac mitochondria contain at least two Ca2+-activated influx mechanisms, a mitochondrial ryanodine receptor that operates most effectively in the lower ranges (<50 ^M) of Ca2+ and a Ca2+ uniporter that operates most effectively in higher ranges of Ca2+. These two Ca2+ transporters sequester Ca2+ proficiently and complementarity for regulating Ca2+ homeostasis, ATP production, and reactive oxygen species generation. These mitochondrial Ca2+- mediated functions are achieved physiologically by a concomitant increase in mitochondrial ADP, serving not only as a substrate for ATP production but also an inhibitor for mitochondrial permeability transition pores. In diseased states, this coordinated interaction between Ca2+ and ADP is disrupted and prone the cells to Ca2+- and oxidative stress-mediated injury and death". The four specific aims are: 1) to further characterize the molecular properties of mitochondrial ryanodine receptor, 2) to evaluate the distinct role of mitochondrial ryanodine receptor and Ca2+ uniporter in Ca2+ regulation, 3) to determine the modulation of mitochondrial Ca2+ uptake by redox environments, and 4) to elucidate the role of mitochondrial Ca2+ and ADP in balancing cellular ATP generation and Ca2+ homeostasis in healthy and cardiomyopathic hearts. Working closely with our collaborators, we will use multidisciplinary approaches encompassing cell biology, biochemistry, biophysics, and molecular biology, to elucidate the molecular and functional characteristicsof mitochondrial Ca2+ influx mechanisms. Recent studies of diseases caused by either mitochondrial DNA mutations or mitochondrial dysfunction all suggest that Ca2+ deregulation is most critical. Some examples of such diseases are cardiomyopthy in chronic heart failure, ischemic heart disease, neurodegenerative diseases, diabetics, obesity, and aging. Therefore, completion of our research aims will not only to have a significant impact on our understanding of basic mechanisms in the etiology of mitochondria-mediated diseases, but also on our strategies in developing the therapeutic means for treating these diseases.