Short talk:
Cutting RNA to power life: Molecular basis of RNA processing in human mitochondria

Hauke Hillen1,2, Arjun Bhatta1,2

1University Medical Center Göttingen, Department of Cellular Biochemistry, Göttingen, Germany,
2Max-Planck-Institute for Multidisciplinary Sciences, Research Group Structure and Function of Molecular Machines, Göttingen, Germany

Mitochondria contain an organellar genome, which is expressed by dedicated molecular machineries that differ from those found in other cellular compartments or in bacteria. We have previously elucidated the structural basis of transcription in human mitochondria (Hillen et al., Cell 2017a, 2017b). However, the mechanisms of RNA processing and maturation in human mitochondria remain poorly understood. The mitochondrial RNA polymerase produces polycistronic transcripts that contain mRNAs and rRNAs flanked by tRNAs, which need to be processed to liberate the individual RNA species. The first step of RNA processing is carried out by mitochondrial RNase P (mtRNase P), which cleaves the transcripts at the 5’ end of tRNAs. In contrast to most other RNase P enzymes, human mtRNase P is not a ribozyme and is instead comprised of three protein subunits that carry out both pre-tRNA cleavage and methylation. We have recently determined the cryo-EM structure of human mtRNase P bound to pre-tRNA, which reveals the mechanism of this dual-function RNA processing machine (Bhatta et al., NSMB 2021). The subunits MRPP1 and MRPP2 form a subcomplex that interacts with conserved elements in mitochondrial tRNAs, including the anticodon loop, by a unique mechanism and positions the pre-tRNA for methylation. The endonuclease MRPP3 is recruited and activated through interactions with its PPR and nuclease domains, which ensures precise cleavage of the pre-tRNA. Mapping of disease mutations to the structure additionally provides insights into the molecular basis of human mitochondrial disorders. These results reveal the molecular mechanism of the first step of mitochondrial RNA processing, and provide a framework for studying mitochondrial RNA metabolism.

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