Clu forms a dynamic new ribonucleoprotein particle directly involved in mitochondrial function

项目概述：功能齐全的线粒体对细胞至关重要， 对于需要高能量的组织，如肌肉、神经元和发育中的胚胎来说很重要。作为 这样的线粒体功能障碍通常与疾病相关，例如神经变性、心血管 疾病和糖尿病。线粒体与细胞核协同工作，必须输入数百个细胞核- 编码产物来补充它们自己的小基因组。我们把果蝇作为一个模型系统， 研究线粒体，我们的长期目标是了解控制线粒体的分子机制。 线粒体在组织稳态和发育过程中的功能。我们发现果蝇蛋白质 Clu是支持线粒体功能所必需的。Clu从酵母到人类高度保守， Clu家族成员是核糖核蛋白，其优先结合细胞核编码的mRNA， 线粒体Clu在细胞质中形成动态的、大的、与线粒体相关的颗粒。我们广泛 该提案的目标是确定颗粒如何形成以及它们在支持中发挥什么作用。 线粒体功能和蛋白质输入。果蝇的clu突变体是病态和不育的， 线粒体Clu与位于线粒体外膜的蛋白质结合，包括 负责蛋白质输入的转位酶。Clu还与外膜上的核糖体结合。我们 假设Clu颗粒形成对于调节mRNA定位和蛋白质输入是重要的。 为了验证这一假设，我们的第一个目标定义了Clu粒子动力学和调节它的信号， 显微镜、遗传学和分子生物学。我们的第二个目的是研究Clu颗粒如何促进mRNA 调节使用显微镜，分子生物学和生物化学。我们的第三个目标使用分子生物学， 生物化学和遗传学来研究Clu颗粒如何调节线粒体蛋白质水平。知识 我们希望从这个关于Clu粒子调节的提案中获得的好处将是向前迈出的变革性一步，因为 对参与线粒体蛋白输入的核糖核蛋白和Clu颗粒知之甚少 代表一种未定义的、对线粒体功能至关重要的新型细胞质颗粒。获得的消息 这里提出的研究将大大促进我们对美洲狮如何本地化的理解， mRNA被调节、翻译和输入，这是一个基本的、根本的过程，对于 所有细胞中的线粒体功能。

PROJECT SUMMARY: Fully functional mitochondria are critically important for cells, and particularly important for tissues with high-energy demands such as muscle, neurons, and the developing embryo. As such, mitochondrial dysfunction is often associated with disease, such as neurodegeneration, cardiovascular disease and diabetes. Mitochondria work in concert with the nucleus and must import hundreds of nucleus- encoded products to supplement their own small genome. We have developed Drosophila as a model system to study mitochondria and our long-term goal is to understand the molecular mechanisms that control mitochondrial function during tissue homeostasis and development. We have found the Drosophila protein Clueless (Clu) is required to support mitochondrial function. Clu is highly conserved from yeast to human and Clu family members are ribonucleoproteins that preferentially bind nucleus-encoded mRNAs destined for mitochondria. Clu forms dynamic, large, mitochondria-associated particles in the cytoplasm. Our broad objectives for this proposal are to determine how particles form and what role they play in supporting mitochondrial function and protein import. Drosophila clu mutants are sick and sterile with damaged mitochondria. Clu associates with proteins located in the mitochondrial outer membrane, including the translocase responsible for protein import. Clu also associates with the ribosome at the outer membrane. We hypothesize that Clu particle formation is important for regulating mRNA localization and protein import. To test this hypothesis, our first Aim defines Clu particle dynamics and the signals that regulates it using microscopy, genetics and molecular biology. Our second Aim examines how Clu particles contribute to mRNA regulation using microscopy, molecular biology and biochemistry. Our third Aim uses molecular biology, biochemistry and genetics to examine how Clu particles regulate mitochondrial protein levels. The knowledge we expect to gain from this proposal on Clu particle regulation will be a transformative step forward because so little is known about the ribonucleoproteins involved in mitochondrial protein import, and Clu particles represent an undefined, novel cytoplasmic particle critical for mitochondrial function. Knowledge gained from the research proposed here will significantly advance our understanding of how mitochondria-localized mRNAs are regulated, translated and imported, which is a basic, fundamental process important for mitochondrial function in all cells.