Maintaining mitochondrial ribosome function: The role of ribosome rescue and recycling factors

Abstract

The universally conserved process of protein biosynthesis is crucial for maintaining cellular homoeostasis and in eukaryotes, mitochondrial translation is essential for aerobic energy production. Mitochondrial ribosomes (mitoribosomes) are highly specialized to synthesize 13 core subunits of the oxidative phosphorylation (OXPHOS) complexes. Although the mitochondrial translation machinery traces its origin from a bacterial ancestor, it has acquired substantial differences within this endosymbiotic environment. The cycle of mitoribosome function proceeds through the conserved canonical steps of initiation, elongation, termination and mitoribosome recycling. However, when mitoribosomes operate in the context of limited translation factors or on aberrant mRNAs, they can become stalled and activation of rescue mechanisms is required. This review summarizes recent advances in the understanding of protein biosynthesis in mitochondria, focusing especially on the mechanistic and physiological details of translation termination, and mitoribosome recycling and rescue.

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

“…It is currently unknown which factor acts upstream of C12ORF65-MTRES1 allowing the dissociation of the ribosome into the subunits. Besides the canonical recycling system composed of mtRRF and mtEFG2, the alternative recycling factor GTPBP6 is a potential candidate to be part of the mitochondrial ribosome rescue system 5,30,31 . However, both recycling pathways do not prefer ribosomes with a peptidyl tRNA in the P-site.…”

“…Both factors share the highly conserved GGQ motif within domain 3 that reaches into the PTC during termination and is essential for facilitating peptide hydrolysis. As mitochondria evolved from an a-proteobacterial ancestor, the human mitochondrial translation machinery reveals similarities to its bacterial counterpart, but also significant differences 5 . Human mitochondria use a slightly different genetic code, e.g.…”

“…The function of the fourth member mtRF1 remains a mystery since it was discovered in 1998 9,10 . It is an open question why do human mitochondria retain mtRF1, if mtRF1a is able to terminate all thirteen mtDNA-encoded peptides 5,16 . Compared to canonical RF1 and mtRF1a, mtRF1 shows insertions in the codon recognition motifs: a PEVGLS hexapeptide instead of the PxT tripeptide motif and an insertion of two amino acids (RT) in the a-5 helix (Fig.…”

Cytochrome c oxidase biogenesis – from translation to early assembly of the core subunit COX1

“…While at least 25 factors have been identified in the cytosol, 12 factors, which show not only similarities but also differences to bacterial translation factors, seem to suffice for mitochondrial translation. These are the initiation factors mtIF2 and mtIF3, the elongation factors mtEFTu, mtEFTs, and mtEFG1, and the mitochondrial release factors mtRF1 and mtRF1a [6,[8][9][10][12][13][14]. Finally, the mitochondrial ribosome is getting dissociated into its subunits by mtRRF and mtEFG2 to be available for the next translation cycle [6,15,16].…”

Molecular basis of translation termination at noncanonical stop codons in human mitochondria

“…1A). Therefore, which factor releases nascent chains at noncanonical stop codons has remained elusive (16). Among previously considered candidates were the mitochondrial release factors ICT1 (mL62, MRPL58) and mtRF-R (C12ORF65) (13,(17)(18)(19); however, it was subsequently established that they are responsible for the rescue of stalled mitoribosomes on truncated mRNAs or after aberrant translation termination (8,13,18,20).…”