Human mitochondria require mtRF1 for translation termination at non-canonical stop codons

The mitochondrial translation machinery highly diverged from its bacterial counterpart. This includes deviation from the universal genetic code, with AGA and AGG codons lacking cognate tRNAs in human mitochondria. The locations of these codons at the end of COX1 and ND6 open reading frames, respecti...

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Published in:	Nature communications Vol. 14; no. 1; p. 30
Main Authors:	Krüger, Annika, Remes, Cristina, Shiriaev, Dmitrii Igorevich, Liu, Yong, Spåhr, Henrik, Wibom, Rolf, Atanassov, Ilian, Nguyen, Minh Duc, Cooperman, Barry S., Rorbach, Joanna
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 03-01-2023 Nature Publishing Group Nature Portfolio
Subjects:	13/106 45/91 49/109 49/90 631/337/1645 631/337/574 82/29 82/58 Codon, Terminator - metabolism Codons Genetic code Genomes Humanities and Social Sciences Humans Medicin och hälsovetenskap Mitochondria Mitochondria - metabolism multidisciplinary Open reading frames Peptide Termination Factors - metabolism Protein Biosynthesis Proteins Ribosomes - metabolism Science Science (multidisciplinary) Stalling Translation Translation termination
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Summary:	The mitochondrial translation machinery highly diverged from its bacterial counterpart. This includes deviation from the universal genetic code, with AGA and AGG codons lacking cognate tRNAs in human mitochondria. The locations of these codons at the end of COX1 and ND6 open reading frames, respectively, suggest they might function as stop codons. However, while the canonical stop codons UAA and UAG are known to be recognized by mtRF1a, the release mechanism at AGA and AGG codons remains a debated issue. Here, we show that upon the loss of another member of the mitochondrial release factor family, mtRF1, mitoribosomes accumulate specifically at AGA and AGG codons. Stalling of mitoribosomes alters COX1 transcript and protein levels, but not ND6 synthesis. In addition, using an in vitro reconstituted mitochondrial translation system, we demonstrate the specific peptide release activity of mtRF1 at the AGA and AGG codons. Together, our results reveal the role of mtRF1 in translation termination at non-canonical stop codons in mitochondria. The mammalian mitochondrial genome contains two noncanonical stop codons, AGA and AGG. Here, the authors show that mtRF1, a mitochondrial protein of unknown function, triggers translation termination at AGA or AGG, placing mtRF1 among mitochondrial translation factors.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-022-35684-6