Molecular analysis of Mdm38 function in mitochondrial protein expression

线粒体维持着一个基因组，编码一小部分蛋白质，其中大多数是非常疏水的，是呼吸链复合体的核心成分。为了表达这些基因，线粒体中维持着转录和翻译机制。线粒体编码蛋白的翻译发生在膜结合的核糖体上，新合成的蛋白通过共翻译的方式插入脂相，例如通过插入酶Oxa1。MDM38是一种高度保守的线粒体内膜蛋白。有趣的是，人类同源基因Letm1与沃尔夫-赫希霍恩综合征的病理有关，这是一种神经退行性疾病。我们发现MDM38与线粒体核糖体相互作用，促进COX1和Cytb mRNAs的翻译。在这方面，MDM38在功能上与核糖体结合蛋白Mba1重叠。Mdm38与mRNA特异性翻译激活物的物理联系表明，mdm38和mba1在将翻译激活物招募到核糖体中可能是重要的。此外，MDM38及其高级真核同源物通过作为K+或Ca~(2+)等阳离子的转运体参与维持线粒体离子的动态平衡。在第二个资助期，我们将确定MDM38-核糖体相互作用的分子基础，以及MDM38如何影响线粒体翻译。因此，我们将对MDM38以及翻译激活子Pet309的蛋白质相互作用网络进行详细的分析。此外，我们将设计策略，从功能上剖析mdm38在核糖体中的任务及其在离子运输中的作用。我们相信，这项研究将为线粒体翻译的调控提供重要的见解，并使我们能够深入了解人类疾病的分子病理学。

Mitochondria have maintained a genome that codes for a small set of proteins, most of which are remarkably hydrophobic and core components of the respiratory chain complexes. To express these genes, transcriptional and translational machineries are maintained in mitochondria. Translation of the mitochondria-encoded proteins takes place on membraneassociated ribosomes and the insertion of the newly synthesized proteins into the lipid phase occurs cotranslationally, e.g. by the insertase Oxa1. Mdm38 is a highly conserved protein of the inner mitochondrial membrane. Interestingly, the human homolog Letm1 has been implicated in the pathology of the Wolf-Hirschhorn syndrome, a neurodegenerative disorder. We found that Mdm38 interacts with mitochondrial ribosomes to promote translation of COX1 and CYTB mRNAs. In this regard Mdm38 functionally overlaps with the ribosome-binding protein Mba1. A physical association of Mdm38 with mRNA specific translational activators suggests that Mdm38 and Mba1 could be important for recruiting translational activators to ribosomes. In addition, Mdm38 and its higher eukaryotic homologous have been implicated in maintaining mitochondrial ion homeostasis by acting as transporters for cations such as K+ or Ca2+. In the second funding period we will determine the molecular basis of the Mdm38- ribosome interaction and how Mdm38 affects mitochondrial translation. Therefore, we will perform detailed analyses of the protein interaction network of Mdm38 as well as of the translational activator Pet309. Moreover, we will device strategies to functionally dissect Mdm38 with regard to its task at the ribosome and its role in ion transport. We believe that this study will provide important insight into the regulation of mitochondrial translation and allow insight into the molecular pathology of a human disorder.