Mitochondrial Ca2+ Transport in Heart Cells

本研究的长期目标是阐明线粒体Ca 2+转运的机制， 在生理和病理条件下的心肌细胞。了大量的研究 提示线粒体Ca ~（2+）在控制细胞内Ca ~（2+）稳态、能量代谢和细胞内Ca ~（2+）代谢中起关键作用 代谢和凋亡。然而，很少有人知道的分子身份和功能的差异， 线粒体Ca 2+转运蛋白。我们的中心假设是“心脏线粒体至少含有两个 Ca 2+激活的内流机制是一种线粒体ryanodine受体，在心肌细胞中最有效地发挥作用。 较低范围（<50 μ M）的Ca 2+和Ca 2+单向转运蛋白，最有效地运作在较高范围的Ca 2 + Ca2+。这两种Ca 2+转运蛋白能够高效地螯合Ca 2+，并互补调节Ca 2 + 体内平衡、ATP产生和活性氧产生。这些线粒体Ca 2 +- 介导的功能在生理上是通过线粒体ADP的伴随增加来实现的， 不仅作为ATP产生的底物，而且作为线粒体通透性转换孔的抑制剂。在 在疾病状态下，Ca 2+和ADP之间的这种协调相互作用被破坏，并使细胞倾向于 Ca 2+和氧化应激介导的损伤和死亡”。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）评估线粒体Ryanodine受体的不同作用， Ryanodine受体和Ca ~（2+）单向转运体在Ca ~（2+）调节中的作用; 通过氧化还原环境的Ca 2+摄取，以及4）阐明线粒体Ca 2+和ADP在 在健康和心肌病心脏中平衡细胞ATP生成和Ca 2+稳态。工作 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 线粒体Ca 2+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Ca 2+失调是最关键的。一些示例 慢性心力衰竭中的心肌病、缺血性心脏病、神经退行性心脏病、 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 这对我们理解大肠杆菌介导的 我们不仅关注疾病，而且关注我们开发治疗这些疾病的治疗方法的策略。

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.