Molecular basis and cellular roles of mitochondria-ER contact sites

家长补助金 5R37GM097432 的摘要： 线粒体在真核细胞中执行基本功能，包括 ATP 生成 通过呼吸和细胞离子和磷脂稳态。他们还充当 整合细胞死亡和先天免疫等信号通路的平台。 线粒体功能与线粒体形式紧密相关，通过以下方式建立： 独立但以某种方式协调的机器，控制动力学、定位、运动 和线粒体 DNA (mtDNA) 传输。内质网（ER）具有 成为线粒体形式调节中不可或缺的普遍参与者 功能。 ER 通过与线粒体接触发挥其作用，我们假设 创建专门的微域，它可以招募和/或调节控制的效应器 并将线粒体生理学与其他细胞器和信号通路整合起来。在 然而，大多数情况下，内质网-线粒体接触的分子组成很差 定义及其确切的作用机制、功能范围和模式 沟通理解甚少。为了实现这笔赠款的目标，我们将解决这些问题 通过探索不同类型 ER-的分子基础和功能来弥补缺陷 酵母中的线粒体接触位点，我们将把我们的发现扩展到哺乳动物细胞 使用比较和前瞻性策略。细胞生物学这一领域的新信息将 深入了解 ER 联系人的一般架构和角色及其监管 线粒体功能和细胞稳态，以更准确地揭示线粒体的作用 线粒体在由线粒体和内质网功能障碍引起的人类疾病中的作用。

Abstract of parent grant 5R37GM097432: Mitochondria perform fundamental functions in eukaryotic cells, including ATP production via respiration and cellular ion and phospholipid homeostasis. They also serve as platforms to integrate signaling pathways such as cell death and innate immunity. Mitochondrial functions are tightly linked to mitochondrial form, established through separate, but somehow coordinated machines that control dynamics, positioning, motility and mitochondrial DNA (mtDNA) transmission. The endoplasmic reticulum (ER) has emerged as an integral and pervasive player in the regulation of mitochondrial form and function. The ER exerts its role through contacts with mitochondria, which we hypothesize create specialized microdomains, which can recruit and/or modulate effectors that control and integrate mitochondrial physiology with other organelles and signaling pathways. In most cases, however, the molecular composition of ER-mitochondria contacts is poorly defined and their exact mechanisms of action, their functional scope and modes of communication are poorly understood. In the aims of this grant, we will address these deficits by exploring the molecular basis and functions of different types of ER- mitochondria contact sites in yeast and we will extend our findings to mammalian cells using comparative and forward strategies. New information in this area of cell biology will provide insight into the general architecture and roles of ER contacts and their regulation of mitochondrial function and cellular homeostasis to more accurately reveal role of mitochondria in human diseases that result from mitochondrial and ER dysfunction.