ROLE OF MIRO SIGNALING FOR AXONAL TRANSPORT OF MITOCHONDRIA

MIRO 信号传导在线粒体轴突运输中的作用

• 批准号: 8269859
• 负责人: KONRAD ERNST ZINSMAIER
• 金额: $ 32.17万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269859
• 关键词: Affect; Autophagocytosis; Axon; Axonal Transport; Binding; Biological Models; Biology; C-terminal; Cells; Complex; Coupled; Defect; Dendrites; Development; Disease; Distal; Docking; Drosophila genus; Dynein ATPase; EF Hand Motifs; Ensure; Event; Exhibits; Genetic; Goals; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Health; ITPR1 gene; Impairment; Kinesin; Link; Lipids; Maintenance; Mediating; Membrane Potentials; Mitochondria; Molecular; Motion; Motor; Mutation; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurons; Neuropathy; Paraplegia; Pathology; Pathway interactions; Phenotype; Protein Isoforms; Proteins; Residencies; Role; Signal Transduction; Site; Structure; Synapses; Synaptic Transmission; System; Testing; Time; Translations; Transmembrane Domain; anterograde transport; genetic analysis; insight; mutant; neuronal cell body; neuronal excitability; neuronal survival; parkin gene/protein; prevent; response; retrograde transport; rho; scaffold

DESCRIPTION (provided by applicant): Supplying axons, dendrites, and synapses with mitochondria is vital for sustaining neuronal excitability and synaptic transmission. In contrast to most other cells, mitochondrial transport is critical for neuronal survival, as impaired transport causes the same pathology as impaired mitochondrial function. A combination of the large distance between soma and synapses, the complexity of neuronal branches, the need to relocate mitochondria in response to changes in neuronal activity, coupled with the need of mitochondria to eventually return to the cell body requires a transport system that is sensitive to pathways communicating the "energetic state of the neuron" and the "state of the mitochondrion". However, we know little about the link between mitochondrial transport and mechanisms that maintain mitochondrial function in axons. A better understanding is urgently needed because even slight impairments of mitochondrial function and/or distribution can cause or intensify neuropathy, neurodegeneration, and/or paraplegia. The evolutionarily conserved mitochondrial GTPase Miro contains two Ca2+ binding domains sandwiched between Rho- and Rab-like GTPase (G) domains. Our genetic analysis shows that mutations in Miro have pleiotropic effects on the biology of mitochondria in axons. We hypothesize that Miro is a central integration node for multimodal signals that controls distinct mechanisms including mitochondrial transport, mitochondrial fusion & fission and autophagy. To test this further, we are taking advantage of the model system Drosophila to elucidate the multiple roles of Miro in neurons by genetically manipulating Miro and its interacting proteins. Aim 1 will characterize how Miro's G1 domain promotes the use of kinesin for anterograde transport and the use of dynein for retrograde transport in axons. Aim 2 will characterize the Ca2+-sensitive role of Miro for mitochondrial function in axons. Aim 3 will characterize the role of Miro for mitochondrial fusion & fission and/or autophagy. The project is expected to reveal critical insights into molecular signaling mechanisms that ensure mitochondrial function in axons. Uncovering these pathways will expand our understanding of logistical mechanisms that are critical for the long-term survival of neurons.

描述(由申请人提供)：提供轴突、树突和与线粒体的突触对于维持神经元的兴奋性和突触传递至关重要。与大多数其他细胞不同，线粒体转运对神经元的生存至关重要，因为线粒体转运受损会导致与线粒体功能受损相同的病理变化。胞体和突触之间的距离很长，神经元分支的复杂性，需要重新定位线粒体以应对神经元活动的变化，再加上线粒体最终返回细胞体的需要，这些因素结合在一起，需要一个运输系统，该系统对传递“神经元的能量状态”和“线粒体的状态”的通路很敏感。然而，我们对线粒体运输和维持轴突线粒体功能的机制之间的联系知之甚少。迫切需要更好的理解，因为即使是线粒体功能和/或分布的轻微损害也会导致或加剧神经病变、神经变性和/或截瘫。进化上保守的线粒体GTP酶MIRO含有两个钙结合结构域，夹在Rho和Rab样GTP酶(G)结构域之间。我们的遗传分析表明，MIRO的突变对轴突中的线粒体生物学具有多效性。我们假设MIRO是多模式信号的中心整合节点，它控制着不同的机制，包括线粒体运输、线粒体融合与裂变和自噬。为了进一步测试这一点，我们正在利用模型系统果蝇，通过遗传操作MIRO及其相互作用的蛋白质来阐明MIRO在神经元中的多种角色。目标1将描述Miro的G1结构域如何促进运动素用于轴突顺行运输和动力蛋白用于轴突的逆行运输。目的2研究MIRO对轴突线粒体功能的钙敏感作用。目标3将描述MIRO在线粒体融合、分裂和/或自噬中的作用。预计该项目将揭示确保轴突线粒体功能的分子信号机制的关键见解。揭示这些途径将扩大我们对对神经元长期生存至关重要的后勤机制的理解。