MTRF1 (mitochondrial translation release factor 1) is a specialized mitochondrial peptide chain release factor that terminates translation at non-canonical stop codons in human mitochondria 1. Unlike the major release factor mtRF1a, which recognizes standard UAA and UAG stop codons, MTRF1 specifically directs termination at the arginine codons AGG and AGA located at the end of MT-CO1/COX1 and MT-ND6/ND6 open reading frames, respectively 123. MTRF1 recognizes these non-canonical stop codons through a previously unknown mechanism that repositions the first two bases of the codon, utilizing an intricate network of interactions involving the release factor protein, ribosomal RNA from the small subunit, and neighboring mRNA bases—distinct from the direct codon-recognition strategy employed by other release factors 3. Loss of MTRF1 causes ribosomal stalling specifically at AGA and AGG codons, leading to isolated cytochrome c oxidase (COX) deficiency and activation of mitochondrial ribosome-associated quality control, which degrades COX1 mRNA to prevent ribosome overload 12. MTRF1 dysfunction impairs respiratory chain assembly and energy production, making it clinically relevant for mitochondrial diseases affecting oxidative phosphorylation 4.