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: 8448704
• 负责人: KONRAD ERNST ZINSMAIER
• 金额: $ 31.03万
• 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/8448704
• 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）：用线粒体提供轴突，树突和突触对于维持神经元兴奋性和突触传播至关重要。与大多数其他细胞相反，线粒体转运对于神经元存活至关重要，因为运输受损会导致与线粒体功能受损相同的病理。 SOMA和突触之间的较大距离，神经元分支的复杂性的结合，需要重新定位线粒体来应对神经元活性的变化，再加上线粒体的需求最终需要返回细胞体，需要一种运输系统，该系统需要一个敏感的通路，即通向“神经元”和“神经元”和MITOCH的途径。但是，我们对线粒体转运与维持轴突中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，因为甚至对线粒体功能和/或分布的轻微损害也会引起或加剧神经病，神经变性和/或瘫痪。进化保守的线粒体GTPase miro含有两个Ca2+结合结构域，这些结构域夹在Rho-和Rab样GTPase（G）域之间。我们的遗传分析表明，米罗的突变对轴突中线粒体生物学具有多效性影响。我们假设MiRO是多模式信号的中央积分节点，该信号控制了不同机制，包括线粒体转运，线粒体融合和裂变和自噬。为了进一步测试，我们利用模型系统果蝇通过遗传操纵miro及其相互作用的蛋白质来阐明神经元中Miro的多重作用。 AIM 1将表征Miro的G1结构域如何促进驱动蛋白用于顺行传输以及使用动力蛋白在轴突中逆行转运的使用。 AIM 2将表征MIRO在轴突中线粒体功能的Ca2+敏感作用。 AIM 3将表征Miro在线粒体融合和裂变和/或自噬中的作用。预计该项目将揭示对确保轴突线粒体功能的分子信号传导机制的关键见解。发现这些途径将扩大我们对神经元长期生存至关重要的后勤机制的理解。