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

Mdm 38是S.人Letm 1的酿酒酵母同源物，Letm 1是一种与沃尔夫-赫希霍恩综合征的发病机制有关的蛋白质。我们已经发现Mdm 38是呼吸链复合物的生物合成所必需的。内膜蛋白Mdm 38与线粒体核糖体相互作用，并参与蛋白质跨线粒体内膜的输出。由于Mdm 38在这些过程中的作用是未知的，因此我们将在本项目中分析Mdm 38在蛋白质转运和复合物组装中的分子功能。因此，我们将在呼吸链复合物组装过程中的MDM 38的功能与在organello方法的基础上的进口和出口分析突变线粒体。一个中心问题是Mdm 38-核糖体缔合的分子功能。因此，我们将剖析Mdm 38与线粒体核糖体的分子相互作用，并分析其他Mdm 38相互作用蛋白，这些蛋白是Mdm 38复合物的一部分。确定Letm 1是否在人类细胞中实现与酵母中的Mdm 38类似的功能将是特别感兴趣的。因此，我们将使用基于RNAi的方法来降低人类细胞中Letm 1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体。我们的分析应该允许新的见解Mdm 38的功能，呼吸链复合物的生物起源和人类疾病的分子基础。

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.