ROLE OF MIRO SIGNALING FOR AXONAL TRANSPORT OF MITOCHONDRIA

描述（由申请人提供）：为轴突、树突和突触提供线粒体对于维持神经元兴奋性和突触传递至关重要。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，因为受损的转运导致与受损的线粒体功能相同的病理。索马和突触之间的大距离、神经元分支的复杂性、响应于神经元活动的变化而重新定位线粒体的需要以及线粒体最终返回细胞体的需要的组合需要对传递“神经元的能量状态”和“神经元的状态”的通路敏感的运输系统。然而，我们对线粒体运输和维持轴突中线粒体功能的机制之间的联系知之甚少。更好的理解是迫切需要的，因为即使是轻微的线粒体功能和/或分布的损害，可以导致或加剧神经病变，神经变性，和/或截瘫。在进化上保守的线粒体GTdR Miro包含两个夹在Rho和Rab样GTdR（G）结构域之间的Ca 2+结合结构域。我们的遗传分析表明，Miro突变对轴突中线粒体的生物学具有多效性影响。我们假设Miro是多模式信号的中心整合节点，控制不同的机制，包括线粒体转运，线粒体融合和裂变以及自噬。为了进一步验证这一点，我们正在利用果蝇模型系统，通过遗传操纵Miro及其相互作用蛋白来阐明Miro在神经元中的多种作用。目的1将描述米罗的G1域如何促进使用驱动蛋白的顺行运输和使用动力蛋白的逆行运输轴突。目的2将描述Miro对轴突线粒体功能的Ca 2+敏感作用。目的3将描述Miro在线粒体融合和分裂和/或自噬中的作用。该项目有望揭示确保轴突中线粒体功能的分子信号机制的关键见解。揭示这些通路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。

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.