Mechanisms controlling mitochondrial division and positioning

控制线粒体分裂和定位的机制

• 批准号: 8320081
• 负责人: Jodi M. Nunnari
• 金额: $ 29.24万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8320081
• 关键词: Acute; Address; Affect; Alzheimer' s Disease; Apoptosis; Axonal Transport; Biochemical; Biochemical Genetics; Cell division; Cells; Cellular biology; Data; Defect; Development; Diabetes Mellitus; Disease; Dynamin; Event; Family; Fostering; GTP Binding; Genetic; Goals; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Homeostasis; Human; Hydrolysis; In Vitro; Infant Mortality; Knowledge; Lead; Link; Mammalian Cell; Mammals; Mediating; Membrane; Mission; Mitochondria; Modeling; Molecular; Molecular Genetics; Mus; Myocardial Infarction; Nerve Degeneration; Neurons; Nuclear; Organelles; Orthologous Gene; Parkinson Disease; Pathway interactions; Positioning Attribute; Post-Translational Protein Processing; Process; Proteins; Proteomics; Reaction; Regulation; Research; Resolution; Role; Signal Pathway; Stationary Populations; Stroke; Structure; Testing; Therapeutic; Work; Yeasts; base; cell cortex; cell type; constriction; human disease; in vivo; insight; mitochondrial membrane; neuron loss; new therapeutic target; protein function; receptor; therapeutic target

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. )

描述（由申请人提供）：线粒体划分通过保守的DRP的作用，介导线粒体的细胞内分布与运输和束缚途径。线粒体划分的调节至关重要；线粒体过度分裂与包括神经变性在内的许多疾病有关。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分发线粒体并有助于细胞稳态。使用结构，生化，遗传和细胞学方法在酵母和哺乳动物细胞中的结合，我们将解决一个杰出的问题，即分子水平划分如何利用GTPase循环以分裂线粒体。尽管DRP可以在体外充当最小机器，但在细胞中，所有DRP都需要其他蛋白质，其作用机理尚不清楚。我们将确定线粒体分裂DRP效应蛋白如何在酵母和哺乳动物细胞中发挥作用。这将提供新的见解，以了解它们如何用于将线粒体功能与细胞信号通路集成在一起，并选择调节非传统的DRP细胞事件（例如凋亡）。我们将通过分析DNM1相互作用的蛋白NUM1来确定DRP如何用于不同活性，该蛋白是一种介导线粒体束缚的皮质蛋白。我们对NUM1的关注也将有助于填补我们对基于绑扎的分布的分子基础的差距，该分布在细胞类型中很常见，例如具有功能上重要的固定线粒体群体的神经元。线粒体分裂和分布的基本机制及其调节与我们对越来越多的疾病的分子基础的理解直接相关，例如帕金森氏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状况的新的，更好的治疗策略铺平道路。 ）