Rescuing stalled mammalian mitoribosomes – what can we learn from bacteria?

Abstract

In the canonical process of translation, newly completed proteins escape from the ribosome following cleavage of the ester bond that anchors the polypeptide to the P-site tRNA, after which the ribosome can be recycled to initiate a new round of translation. Not all protein synthesis runs to completion as various factors can impede the progression of ribosomes. Rescuing of stalled ribosomes in mammalian mitochondria, however, does not share the same mechanisms that many bacteria use. The classic method for rescuing bacterial ribosomes is trans-translation. The key components of this system are absent from mammalian mitochondria; however, four members of a translation termination factor family are present, with some evidence of homology to members of a bacterial back-up rescue system. To date, there is no definitive demonstration of any other member of this family functioning in mitoribosome rescue. Here, we provide an overview of the processes and key players of canonical translation termination in both bacteria and mammalian mitochondria, followed by a perspective of the bacterial systems used to rescue stalled ribosomes. We highlight any similarities or differences with the mitochondrial translation release factors, and suggest potential roles for these proteins in ribosome rescue in mammalian mitochondria.

Ribosome Rescue Pathways in Bacteria

“…ArfB and ICT1 are functionally interchangeable in vivo, since ICT1 can complement the synthetic lethal phenotype of double deletion of ArfB and trans-translation in C. crescentus, and plasmid derived ArfB supports viability of human cells upon ICT1 knockdown (Feaga et al, 2016). However, whether ICT1 or another putative mitochondrial peptidyl-hydrolase releases non-stop complexes in mitochondria remains contentious (Richter et al, 2010;Duarte et al, 2012;Akabane et al, 2014;Chrzanowska-Lightowlers and Lightowlers, 2015;Takeuchi and Nierhaus, 2015;Ayyub et al, 2020).…”

Elongational stalling activates mitoribosome-associated quality control

“…In these and other cases, RQC is critical to maintain cellular homeostasis by rescuing stalled ribosomes, preventing protein misfolding and other aberrant translation phenotypes (8,9). Mitochondria, however, lack counterparts to bacterial rescue mechanisms such as trans-translation, strin-gent control, and ArfA (10). ICT1, the presumed mitochondrial ortholog of another bacterial rescue factor, ArfB, was instead identified as an integral component of the LSU (1,3,11).…”

“…ICT1, the presumed mitochondrial ortholog of another bacterial rescue factor, ArfB, was instead identified as an integral component of the LSU (1,3,11). In silico studies have proposed that other putative mitochondrial release factors may exist in addition to the canonical termination factor mtRF1a, but without biochemical evidence (10).…”

“…The importance of this rescue pathway is highlighted by the facts that mtRF-R is essential for mitochondrial protein synthesis (19, 20) and that mutations lead to human disease phenotypes, especially the triad of optic atrophy, peripheral neuropathy, and spastic paraparesis (10). Autosomal recessive mutations result in mtRF-R truncations, the extent of which largely, but not exclusively, correlates with severity of disease (17,19,20) (fig.…”

MTALTND4, a second protein coded by nd4 impacts mitochondrial bioenergetics

“…2 A-E ). The mtaltnd4 altORF is 300 nucleotides long and code for a putative 99 amino-acid peptide (with no predicted transmembrane helix) using the mitochondrial vertebrate genetic code and considering that human mitochondria use only UAA and UAG as stop codons as recently suggested ( 12, 13 ) (Fig. 2 A and table S1; see supplementary text 1).…”