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

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Abstract

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.

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  1. Review coordinated via ASAPbio’s crowd preprint review

    This review reflects comments and contributions by Ruchika Bajaj, Pablo Ranea-Robles and Michael Robichaux. Review synthesized by Michael Robichaux.


    The manuscript reports findings from new knockout human cell lines for the mitochondrial release factors mtRF1 and mtRF1a. The work contributes new insight into mitochondrial protein translation and mechanisms related to mitochondrial disease. A specific role is demonstrated for the release factor mtRF1 in the translation of COX1, a mitochondrial respiratory protein. The manuscript also identified a compensatory role for the mitochondrial ribosome-associated quality control (mtRQC) pathway when mitochondrial translation termination is impaired.

    Overall the experiments and results presented in the manuscript are supportive of the …