How do neurons maintain mitochondrial homeostasis in vivo?

项目摘要 线粒体对神经元的功能至关重要，必须可靠地分布在整个神经元中。至 维持健康、适当分布的线粒体，神经元必须协调线粒体的动态， 包括运动性，裂变和聚变，以及随时间和空间的退化。这项提案的总体目标是 明确在体神经元线粒体动力学的时空调控机制。为此，我们 将使用一种创新的活体成像方法来测量明确运动的线粒体动力学 果蝇的视觉神经元。通过将我们的体内测量与数学建模相结合，我们将 从机制上洞察神经元如何在系统水平上维持线粒体的动态平衡。我们 提出三个具体目标。在目标1中，我们将确定神经元如何维持稳定状态的线粒体 尽管线粒体运动水平很高，但在复杂的神经元形态中的分布模式。 具体地说，我们将检验这样一个假设，即神经元结构为稳健的自我- 特定线粒体定位模式的组织。我们将使用体内的实验测量 线粒体运动性和神经元分支模式发展一个连接大尺度的量化模型 线粒体分布到分支的比例规则。我们将通过预测线粒体来测试这个模型 神经细胞结构的实验测量在形态和结构上的定位模式 功能多样的果蝇视觉系统神经元。然后我们将通过比较以下各项来测试我们的模型预测 EM数据集中线粒体分布的地面真实测量。在目标2中，我们将研究如何 适当的时空控制线粒体的分裂和融合有助于维持健康 远端轴突和树突中的线粒体。我们将检验神经元优化分裂和融合的假设 既能最大限度地提高线粒体的互补性，又能确保高效传递新的- 合成线粒体蛋白质至远端轴突和树突。最后，在目标3中，我们将探讨 活体神经元的活性和吞丝率之间的关系。总而言之，这项提案承诺提供 一个关键的机制框架，用于了解神经元如何调节线粒体运动、分裂和 融合和降解，以维持体内健康、适当分布的线粒体群体，提供 对神经退行性疾病的分子和细胞基础的新见解。

Project Summary Mitochondria are critical for neuronal function and must be reliably distributed throughout the entire neuron. To maintain healthy, properly distributed mitochondria, neurons must coordinate mitochondrial dynamics, including motility, fission and fusion, and degradation, over space and time. The broad goal of this proposal is to define mechanisms for spatiotemporal control of mitochondrial dynamics in neurons in vivo. To that end, we will employ an innovative in vivo imaging approach to measure mitochondrial dynamics in well-defined motion vision neurons in Drosophila. By combining our in vivo measurements with mathematical modeling, we will gain mechanistic insight into how neurons maintain mitochondrial homeostasis at the systems level. We propose three specific aims. In Aim 1 we will determine how neurons maintain steady-state mitochondrial distribution patterns despite high levels of mitochondrial motility within complex neuronal morphologies. Specifically, we will test the hypothesis that neuronal architectures are optimized for the robust self- organization of specific mitochondrial localization patterns. We will use experimental measurements of in vivo mitochondrial motility and neuronal branching patterns to develop a quantitative model linking large-scale mitochondrial distributions to branch scaling rules. We will test this model by predicting mitochondrial localization patterns from experimental measurements of neuronal architecture across morphologically and functionally diverse Drosophila visual system neurons. We will then test our model predictions by comparing to ground truth measurements of mitochondrial distributions in EM datasets. In Aim 2 we will investigate how proper spatiotemporal control of mitochondrial fission and fusion contributes to the maintenance of healthy mitochondria in distal axons and dendrites. We will test the hypothesis that neurons optimize fission and fusion rates to both maximize complementation across mitochondria and ensure efficient delivery of newly- synthesized mitochondrial proteins to distal axons and dendrites. Finally, in Aim 3 we will probe the relationship between neuronal activity and mitophagy rates in neurons in vivo. Altogether, this proposal promises to provide a critical mechanistic framework for understanding how neurons regulate mitochondrial movement, fission and fusion, and degradation to maintain healthy, properly distributed mitochondrial populations in vivo, providing new insight into the molecular and cellular basis for neurodegenerative diseases.