Mechanisms controlling mitochondrial division and positioning

描述（由申请人提供）：线粒体分裂，通过保守的DRP的作用，介导线粒体的细胞内分布，与运输和拴系途径一致。线粒体分裂的调节至关重要;过度的线粒体分裂与许多疾病有关，包括神经变性。我们的长期目标是了解线粒体分裂的机制和调节，以及分裂蛋白如何与其他途径合作来分配线粒体并有助于细胞内稳态。在酵母和哺乳动物细胞中使用结构，生物化学，遗传和细胞学方法的组合，我们将解决如何在分子水平上分裂DRPs利用GTdR循环分裂线粒体的突出问题。尽管DRPs在体外可以作为最小的机器发挥作用，但在细胞中都需要额外的蛋白质，其作用机制还不清楚。我们将确定线粒体分裂DRP效应蛋白在酵母和哺乳动物细胞中的机制功能。这将为它们如何用于整合线粒体功能与细胞信号传导途径以及如何被选择用于调节非传统DRP细胞事件（如细胞凋亡）提供新的见解。我们将通过分析Dnm 1相互作用蛋白Num 1（一种介导线粒体束缚的皮质蛋白）来确定DRPs如何用于不同的活动。我们对Num 1的关注也将有助于填补我们对基于拴系的分布的分子基础的理解中的差距，这在细胞类型中很常见，例如具有功能重要的固定线粒体群体的神经元。线粒体分裂和分布及其调节的基本机制与我们对越来越多疾病的分子基础的理解直接相关，例如帕金森病和糖尿病以及急性病理状况，例如中风和心脏病发作。因此，这项工作将为人类这些疾病和病症的新的和更好的治疗策略铺平道路。)

DESCRIPTION (provided by applicant): Mitochondrial division, through the action of a conserved DRP, mediates the intracellular distribution of mitochondria in concert with transport and tethering pathways. Regulation of mitochondrial division is critical; excessive mitochondrial division is linked to numerous diseases, including neurodegeneration. Our long-term goal is to understand the mechanism and regulation of mitochondrial division and how division proteins collaborate with other pathways to distribute mitochondria and contribute to cellular homeostasis. Using a combination of structural, biochemical, genetic, and cytological approaches in yeast and mammalian cells, we will address the outstanding question of how on the molecular level division DRPs harness the GTPase cycle to divide mitochondria. Although DRPs can function as minimal machines in vitro, in cells all require additional proteins, whose mechanisms of action are not well understood. We will determine how mitochondrial division DRP effector proteins mechanistically function in yeast and mammalian cells. This will provide new insight into how they are used to integrate mitochondrial functions with cellular signaling pathways and are co-opted to regulate non-traditional DRP cellular events, such as apoptosis. We will determine how DRPs are harnessed for different activities through the analysis of the Dnm1 interacting protein, Num1, which is a cortical protein that mediates mitochondrial tethering. Our focus on Num1 will also serve to fill the gap in our understanding of the molecular basis of tethering-based distribution, which is common in cell types, such as neurons that have a functionally important population of stationary mitochondria. The basic mechanisms of mitochondrial division and distribution and their regulation are directly relevant to our understanding of the molecular basis of an increasing number of diseases, such as Parkinson's disease and diabetes and also acute pathological conditions, such as stroke and heart attack. As such, this work will pave the way for new and better therapeutic strategies for these diseases and conditions in humans. )