Mechanisms controlling mitochondrial division and positioning

控制线粒体分裂和定位的机制

• 批准号: 8087874
• 负责人: Jodi M. Nunnari
• 金额: $ 29.17万
• 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/8087874
• 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. ) PUBLIC HEALTH RELEVANCE: ) Understanding the fundamental mechanism of division and its regulation is directly relevant to understanding the basis of an increasing number of diseases associated with defects in mitochondrial division, such as Alzheimer's, Parkinson's and diabetes. The links between mitochondrial division and disease and between division proteins and apoptosis makes these proteins attractive targets for new therapeutics. Thus, the proposed research is relevant to the part of the NIH's mission that fosters fundamental basic cell biology discoveries that will directly lead the development of potentially new classes of therapeutics that target division to treat a wide array of human diseases.

描述（由申请人提供）：线粒体分裂，通过保守DRP的作用，介导线粒体的细胞内分布，与运输和栓系途径一致。线粒体分裂的调控至关重要；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控，以及分裂蛋白如何与其他途径合作分布线粒体并促进细胞稳态。利用酵母和哺乳动物细胞的结构、生化、遗传和细胞学方法的结合，我们将解决在分子水平上分裂DRPs如何利用GTPase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，其作用机制尚不清楚。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。这将为研究它们如何将线粒体功能与细胞信号通路整合，以及如何调节非传统DRP细胞事件（如凋亡）提供新的见解。我们将通过分析Dnm1相互作用蛋白Num1来确定DRPs如何被用于不同的活动，Num1是一种介导线粒体拴系的皮质蛋白。我们对Num1的关注也将有助于填补我们对基于系绳分布的分子基础的理解的空白，系绳分布在细胞类型中很常见，例如具有重要功能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控与我们对越来越多疾病（如帕金森病和糖尿病）以及急性病理状况（如中风和心脏病发作）的分子基础的理解直接相关。因此，这项工作将为人类这些疾病和病症的新的更好的治疗策略铺平道路。