Molecular function of Mdm38 in protein export and biogenesis of respiratory chain complexes of the inner mitochondrial membrane

Mdm38是酿酒葡萄球菌与人类Letm1的同源物，Letm1是一种与狼-赫希霍恩综合征发病机制有关的蛋白质。我们已经发现Mdm38是呼吸链复合体的生物发生所必需的。内膜蛋白Mdm38与线粒体核糖体相互作用，参与蛋白质穿过线粒体内膜的输出。由于Mdm38在这些过程中的作用尚不清楚，我们将在本项目中分析Mdm38在蛋白质运输和复合物组装中的分子功能。因此，我们将利用基于突变体线粒体输入和输出分析的细胞器方法来研究Mdm38在呼吸链复合体组装过程中的功能。核心问题是mdm38 -核糖体结合的分子功能。因此，我们将剖析Mdm38与线粒体核糖体的分子相互作用，并分析其他Mdm38相互作用蛋白，它们是Mdm38复合物的一部分。确定Letm1是否在人类细胞中实现与Mdm38在酵母中的相似功能将是特别有趣的。因此，我们将使用基于RNAi的方法来降低人类细胞中Letm1的水平，并分析这些细胞中的线粒体功能，如形态和呼吸链复合物。我们的分析将对Mdm38的功能、呼吸链复合物的生物发生和人类疾病的分子基础提供新的见解。

Mdm38 is the S. cerevisiae homolog of the human Letm1, a protein that has been implicated in the pathogenesis of the Wolf-Hirschhorn Syndrome. We have found that Mdm38 is required for the biogenesis of respiratory chain complexes. The inner membrane protein Mdm38 interacts with mitochondrial ribosomes and participates in protein export across the inner mitochondrial membrane. Since the role of Mdm38 in these processes is unknown, we will analyze the molecular function of Mdm38 in protein transport and complex assembly in this project. Therefore, we will address the function of Mdm38 in the process of respiratory chain complex assembly with an in organello approach based on import and export analyses in mutant mitochondria. A central question is the molecular function of the Mdm38-ribosome association. Therefore, we will dissect the molecular interactions of Mdm38 with mitochondrial ribosomes and analyze other Mdm38 interacting proteins, which are part of the Mdm38 complex. It will be of particular interest to determine if Letm1 fulfills similar functions in human cells as Mdm38 in yeast. Therefore we will use an RNAi based approach to reduce levels of Letm1 in human cells and analyze mitochondrial functions such as morphology and respiratory chain complexes in these cells. Our analysis should allow novel insights into the function of Mdm38, the biogenesis of respiratory chain complexes and the molecular basis of a human disease.