Role of dMiro Signaling for Axonal Transport of Mitochondria

dMiro 信号传导在线粒体轴突运输中的作用

基本信息

批准号：
7405416
负责人：
KONRAD ERNST ZINSMAIER
金额：
$ 29.79万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7405416
关键词：
Acute Adaptor Signaling Protein Aging Apoptosis Axon Axonal Transport Binding Biological Models Cardiomyopathies Cell Respiration Cell membrane Chromosome Pairing Chronic Condition Consumption Coupling Dendrites Development Disease Dominant-Negative Mutation Drosophila genus Dynein ATPase EF Hand Motifs EF-Hand Domain Fractionation Goals Growth Cones Guanosine Triphosphate Phosphohydrolases Homeostasis Image In Situ Individual Intracellular Transport Kinesin Label Life Link Malignant Neoplasms Measures Microtubules Mitochondria Mitochondrial Proteins Molecular Molecular Conformation Motor Motor Activity Motor Neurons Movement Muscular Dystrophies Nerve Nerve Degeneration Neurons Neuropathy Paraplegia Pathway interactions Phenotype Physiological Plastics Plus End of the Microtubule Presynaptic Terminals Protein Overexpression Proteins Role Signal Pathway Signal Transduction Site Stress Synapses System Temperature Testing Time Work base concept dynactin in vivo loss of function mutation mitochondrial membrane mutant prevent respiration regulation response rho sensor synaptic function targeted delivery

项目摘要

DESCRIPTION (provided by applicant): Mitochondria are vital for aerobic respiration, the regulation of Ca2+ homeostasis, apoptosis, aging, and cancer. The intracellular distribution of mitochondria is adaptable to physiological stresses and changes in cellular activity. This plastic control is believed to be especially important in neurons where mitochondria are enriched at regions of intense energy consumption like synapses. Despite the significance of mitochondria for synaptic function, we still do not understand the molecular mechanisms controlling their delivery and targeting to synapses. A comprehensive understanding is urgently needed since abnormal mitochondrial transport, like abnormal mitochondrial function, is associated with various forms of muscular dystrophy, cardiomyopathy, neuropathy, paraplegia, and neurodegeneration. Our previous work suggests that the evolutionary conserved mitochondrial Rho-like GTPase Miro may act as a mitochondrial sensor that integrates intracellular signals to control long-distance transport of mitochondria. Specifically, loss of Drosophila Miro (dMiro) function prevents mitochondrial transport into axons and dendrites while gain of dMiro function leads to an abnormal accumulation of mitochondria at motor nerve terminals. Together, these results suggest dMiro may control anterograde axonal transport and the distribution of mitochondria to synaptic sites. To further test this hypothesis, we will take advantage of the model system Drosophila and genetically manipulate dMiro and other proteins of the mitochondrial transport machinery. Mutant effects on mitochondrial transport will be primarily examined in larval motor neurons, their axons and axon terminals by live imaging of GFP-tagged mitochondria to resolve the following key issues: Aim 1 will resolve whether dMiro promotes net-anterograde axonal transport by increasing the efficiency of microtubules (MT) plus end- or decreasing minus end-directed transport. Aim 2 will determine the role of dMiro's EF-hand Ca2+ binding domains for mitochondrial transport and/or the intracellular distribution of mitochondria. Aim 3 will test the molecular mechanisms by which dMiro may control mitochondrial transport. The proposed project is expected to reveal important molecular signaling mechanisms that regulate the long- distance transport of mitochondria and their use-dependent distribution into synaptic terminals. Uncovering these signaling pathways will significantly expand our understanding of basic mechanisms and accelerate the development of new concepts for detecting, treating, and/or preventing disorders that are caused by defective mitochondrial transport pathways and/or impaired mitochondrial function.

描述（由申请人提供）：线粒体对于有氧呼吸，CA2+稳态，凋亡，衰老和癌症至关重要。线粒体的细胞内分布适应生理应力和细胞活性的变化。人们认为，这种塑料控制在神经元中尤为重要，在神经元中线粒体在强烈的能量消耗区域（如突触）中富集。尽管线粒体对于突触功能的重要性，但我们仍然不了解控制其递送和靶向突触的分子机制。迫切需要一种全面的理解，因为线粒体的异常转运（如线粒体功能异常）与各种形式的肌肉营养不良，心肌病，神经性病，阶段性和神经变性有关。我们以前的工作表明，进化保守的线粒体Rho样GTPase Miro可以充当线粒体传感器，该传感器将细胞内信号整合以控制线粒体的长距离运输。具体而言，果蝇的丧失（DMIRO）功能可防止线粒体转运到轴突和树突中，而DMIRO功能的增益会导致在运动神经终端处线粒体的异常积累。总之，这些结果表明DMIRO可以控制轴突运输和线粒体向突触部位的分布。为了进一步检验这一假设，我们将利用模型系统果蝇，并通过遗传操纵DMIRO和线粒体转运机械的其他蛋白质。 Mutant effects on mitochondrial transport will be primarily examined in larval motor neurons, their axons and axon terminals by live imaging of GFP-tagged mitochondria to resolve the following key issues: Aim 1 will resolve whether dMiro promotes net-anterograde axonal transport by increasing the efficiency of microtubules (MT) plus end- or decreasing minus end-directed transport. AIM 2将确定DMIRO的EF手Ca2+结合结构域在线粒体转运和/或线粒体的细胞内分布中的作用。 AIM 3将测试DMIRO可以控制线粒体转运的分子机制。预计该提出的项目将揭示重要的分子信号传导机制，该机制调节线粒体的长距离运输及其使用依赖性分布到突触末端。揭示这些信号通路将显着扩展我们对基本机制的理解，并加速用于检测，治疗和/或预防由线粒体传输途径和/或线粒体功能受损的疾病的新概念的发展。