Homeostatic Mechanisms Regulating Mitochondrial Health

项目摘要/摘要 线粒体是重要的细胞器，最广为人知的是它是细胞的“动力源”，因为 它们在氧化磷酸化(OXPHOS)和其他代谢途径中的作用。此外，他们还拥有 在细胞生物学的其他领域中的不同作用，包括钙处理、免疫、细胞信号和 形成铁-硫团簇。因此，健康的线粒体对人类健康至关重要，许多 常见疾病与线粒体功能障碍有关。此应用程序的主要目标是 了解控制线粒体健康的机制。有三种特殊的机制 利息。首先，线粒体的功能依赖于融合和分裂的连续循环。这些动态 过程用于使细胞内的线粒体群体同质化，并对维持 线粒体基因组、形态和呼吸链活性。其次，有丝分裂是主要的 识别和移除功能障碍的线粒体的机制。第三，蛋白质监测机制 存在是为了维持产生细胞能量的OXPHOS蛋白质复合体的质量。OXPHOS 复合体由两个基因组编码的蛋白质亚单位组成--核基因组和 线粒体基因组--因此在实现适当的亚基化学计量和 集合。这项研究计划针对的是这三种动态平衡中每一种的知识差距。 机械装置。对于线粒体动力学，本研究计划研究其分子机制。 以及融合和裂变的生理功能。了解分子机制，结构研究 用来获得调节这些过程的关键分子的原子结构。Opa1就是一个例子， 介导内膜融合的分子。关于这种分子如何能够带来 两个内膜结合在一起，并介导膜的合并。为了了解生理功能， 老鼠的研究将被用来确定线粒体融合和裂变的作用。应用程序 重点介绍了两个生物系统--神经系统的星形胶质细胞和雄性生殖细胞--在其中 线粒体分裂和/或有丝分裂起着重要作用。在雄性生殖细胞发育的情况下， 线粒体动力学基因的突变导致明显的阶段特异性缺陷，提供了一种生物学上的 可以破译需要线粒体动力学的多条通路的系统。要理解 如何保持OXPHOS复合体的质量，人类细胞中的创新基因筛选将 被用来识别感知和降解过量亚基的途径。这样的质量控制机制 被牵涉到寿命管理中。综上所述，这些方法将提供一个深刻的 了解维持线粒体健康的动态平衡机制。

Project Summary/Abstract Mitochondria are essential organelles that are most well-known for being cellular "powerhouses," due to their role in oxidative phosphorylation (OXPHOS) and other metabolic pathways. In addition, they have diverse roles in other areas of cell biology, including calcium handling, immunity, cell signaling, and formation of iron-sulfur clusters. Healthy mitochondria are therefore critical for human health, and many common diseases are associated with mitochondrial dysfunction. The broad goal of this application is to understand the mechanisms that control mitochondrial health. There are three mechanisms of particular interest. First, mitochondrial function depends on continual cycles of fusion and fission. These dynamic processes serve to homogenize the mitochondrial population within a cell and are critical for maintenance of the mitochondrial genome, morphology, and respiratory chain activity. Second, mitophagy is a major mechanism to recognize and remove dysfunctional mitochondria. Third, protein surveillance mechanisms exist to maintain the quality of the OXPHOS protein complexes that generate cellular energy. The OXPHOS complexes are composed of protein subunits encoded by two genomes--the nuclear genome and the mitochondrial genome--and therefore have unique challenges in achieving proper subunit stoichiometry and assembly. This research program targets gaps in knowledge in each of these three homeostatic mechanisms. For mitochondrial dynamics, this research program investigates the molecular mechanisms and physiological functions of fusion and fission. To understand molecular mechanism, structural studies are used to obtain atomic structures of the key molecules mediating these processes. An example is Opa1, the molecule that mediates inner membrane fusion. Little is known about how this molecule is able to bring two inner membranes together and mediate membrane merger. To understand physiological function, mouse studies will be used to determine the role of mitochondrial fusion and fission. The application highlights two biological systems--the astrocytes of the nervous system and the male germ cell--in which mitochondrial fission and/or mitophagy play a prominent role. In the case of male germ cell development, mutations in mitochondrial dynamics genes lead to distinct stage-specific defects, providing a biological system in which multiple pathways requiring mitochondrial dynamics can be deciphered. To understand how the quality of the OXPHOS complexes are maintained, innovative genetic screens in human cells will be used to identify pathways that sense and degrade excessive subunits. Such quality control mechanisms have been implicated in lifespan regulation. Taken together, these approaches will provide a deep understanding of homeostatic mechanisms that maintain mitochondrial health.