Human mtRF1 terminates COX1 translation and its ablation induces mitochondrial ribosome-associated quality control

How translation termination is achieved for the non-conventional mtDNA-encoded COX1 and ND6 was so far unknown. Here, Nadler et al. address this question by assessing the functions and specificity of the mitochondrial release factors mtRF1 and mtRF1a. Translation termination requires release factors that read a STOP codon in the decoding center and subsequently facilitate the hydrolysis of the nascent peptide chain from the peptidyl tRNA within the ribosome. In human mitochondria eleven open reading frames terminate in the standard UAA or UAG STOP codon, which can be recognized by mtRF1a, the proposed major mitochondrial release factor. However, two transcripts encoding for COX1 and ND6 terminate in the non-conventional AGA or AGG codon, respectively. How translation termination is achieved in these two cases is not known. We address this long-standing open question by showing that the non-canonical release factor mtRF1 is a specialized release factor that triggers COX1 translation termination, while mtRF1a terminates the majority of other mitochondrial translation events including the non-canonical ND6. Loss of mtRF1 leads to isolated COX deficiency and activates the mitochondrial ribosome-associated quality control accompanied by the degradation of COX1 mRNA to prevent an overload of the ribosome rescue system. Taken together, these results establish the role of mtRF1 in mitochondrial translation, which had been a mystery for decades, and lead to a comprehensive picture of translation termination in human mitochondria.

Automated summary

The study investigates the translation termination mechanism for the non-conventional mtDNA-encoded COX1 and ND6, and identifies mtRF1 as the release factor for COX1 and mtRF1a for other mitochondrial translation events including ND6.