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Mitochondrial RNA maturation and its diseases Johannes Zschocke, Albert Amberger, Andrea Deutschmann Mitochondria are the powerhouses of the cell. They have a central function in energy production and play vital roles in  several cellular processes. Cellular energy is mainly produced by the respiratory protein complexes in mitochondria.  Numerous genetic alterations lead to impaired mitochondrial respiration and result in human pathologies, generally  referred to as “mitochondrial diseases’. Most of the proteins of the respiratory chain are encoded by nuclear DNA;  however, 13 respiratory complex proteins (mRNAs), two ribosomal RNAs (rRNAs) and a complete set of 22 transfer RNAs  (tRNAs) are encoded by mitochondrial DNA (mtDNA), a circular genome inside mitochondria. One essential step in mitochondrial maintenance is mitochondrial RNA (mtRNA) transcript processing. Transcription of  the mtDNA occurs on both DNA strands and produces long polycistronic transcripts of mRNAs and rRNAs, usually  interspersed with tRNAs. Mitochondrial protein translation requires the correct processing of the polycistronic RNA  molecules at the 5´end and 3´end of the interspersed tRNAs to release mature mRNAs, tRNAs, and rRNAs. The initial  processing step, the endonucleolytic cleavage of precursor tRNAs at the 5´end, is performed by RNase P, an enzyme  complex composed of three different proteins (MRPP1, HSD10, and MRPP3). Processing at the 3´end is done by tRNase Z, a single protein coded by the ELAC2 gene. We found that missense mutations in the genes for HSD10 and MRPP3 resulted in reduced tRNA processing which lead to mitochondrial damage due to impaired respiratory complex formation. In HSD10 disease, for instance, patients usually  display a progressive neurodegenerative disease course with loss of cognitive and motor function, epilepsy,  progressive  cardiomyopathy, and  usually death in childhood. Importantly, tRNA processing is the first step in post-transcriptional  mtRNA maturation which includes base modification, RNA surveillance, RNA packaging, and finally RNA decay. It is  estimated that approximately 300 nuclear coded proteins are involved in mitochondrial gene expression and only some of them are known to be involved in mitochondrial disorders. However, there are many unsolved cases of mitochondrial  disease, and defining genetic causes and pathomechanisms remains a major challenge. In our projects, we focus on novel  mutations which disrupt mtRNA biogenesis. Major achievements: Identification, clinical characterization, and functional analysis of HSD10 disease; defining new  defects in mtRNA processing which contribute to mitochondrial disorders. Future goals: Developing diagnostic tools and establishing novel disease models to understand the remarkable  heterogeneity of human mitochondrial diseases caused by defects in mtRNA metabolism.
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