Molecular analysis of Mdm38 function in mitochondrial protein expression

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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.