Of the roughly 1000 human mitochondrial proteins only 13 proteins, all of them hydrophobic inner membrane proteins that are components of the oxidative phosphorylation apparatus, are encoded in the mitochondrial genome and translated by mitoribosomes at the matrix face of the inner membrane (reviewed in Herrmann et al. 2012, Hallberg and Larsson 2014, Lightowlers et al. 2014). The remainder, including all proteins of the mitochondrial translation system, are encoded in the nucleus and imported from the cytosol into the mitochondrion. Translation in the mitochondrion reflects both the bacterial origin of the organelle and subsequent divergent evolution during symbiosis (reviewed in Huot et al. 2014, Richman et al. 2014). Human mitochondrial ribosomes have a low sedimentation coefficient of only 55S, but at 2.71 MDa they retain a similar mass to E. coli 70S particles. The 55S particles are protein-rich compared to both cytosolic ribosomes and eubacterial ribosomes. This is due to shorter mt-rRNAs, mitochondria-specific proteins, and numerous rearrangements in individual protein positions within the two ribosome subunits (inferred from bovine ribosomes in Sharma et al. 2003, Greber et al. 2014, Kaushal et al. 2014, reviewed in Agrawal and Sharma 2012).
Mitochondrial mRNAs have either no untranslated leader or short leaders of 1-3 nucleotides, with the exception of the 2 bicistronic transcripts, RNA7 and RNA14, which have overlapping orfs that encode ND4L/ND4 and ATP8/ATP6 respectively. Translation is believed to initiate with the mRNA binding the 28S subunit:MTIF3 (28S subunit:IF-3Mt, 28S subunit:IF2mt) complex together with MTIF2:GTP (IF-2Mt:GTP, IF2mt:GTP) at the matrix face of the inner membrane (reviewed in Christian and Spremulli 2012). MTIF3 can dissociate 55S particles in preparation for initiation, enhances formation of initiation complexes, and inhibits N-formylmethionine-tRNA (fMet-tRNA) binding to 28S subunits in the absence of mRNA. Binding of fMet-tRNA to the start codon of the mRNA results in a stable complex while absence of a start codon at the 5' end of the mRNA causes eventual dissociation of the mRNA from the 28S subunit. After recognition of a start codon, the 39S subunit then binds the stable complex, GTP is hydrolyzed, and the initiation factors MTIF3 and MTIF2:GDP dissociate.
Translation elongation then proceeds by cycles of aminoacyl-tRNAs binding, peptide bond formation, and displacement of deacylated tRNAs. In each cycle an aminoacyl-tRNA in a complex with TUFM:GTP (EF-Tu:GTP) binds at the A-site of the ribosome, GTP is hydrolyzed, and TUFM:GDP dissociates. The elongating polypeptide bonded to the tRNA at the P-site is transferred to the aminoacyl group at the A-site by peptide bond formation at the peptidyl transferase center, leaving a deacylated tRNA at the P-site and the elongating polypeptide attached to the tRNA at the A-site. The polypeptide is co-translationally inserted into the inner mitochondrial membrane via an interaction with OXA1L (Haque et al. 2010, reviewed in Ott and Hermann 2010). After peptide bond formation, GFM1:GTP (EF-Gmt:GTP) then binds the ribosome complex, GTP is hydrolyzed, GFM1:GDP dissociates, and the ribosome translocates 3 nucleotides in the 3' direction along the mRNA, relocating the polypeptide-tRNA to the P-site and allowing another cycle to begin. TUFM:GDP is regenerated to TUFM:GTP by the guanine nucleotide exchange factor TSFM (EF-Ts, EF-TsMt).
Translation is terminated when MTRF1L:GTP (MTRF1a:GTP) recognizes an UAA or UAG termination codon at the A-site of the ribosome (Tsuboi et al. 2009). GTP hydrolysis does not appear to be required. The tRNA-aminoacyl bond between the translated polypeptide and the final tRNA at the P-site is hydrolyzed by the 39S subunit, facilitating release of the polypeptide. MRRF (RRF) and GFM2:GTP (EF-G2mt:GTP) then act to release the remaining tRNA and mRNA from the ribosome and dissociate the 55S ribosome into 28S and 39S subunits.
Mutations have been identified in genes encoding mitochondrial ribosomal proteins and translation factors. These have been shown to be pathogenic, causing neurological and other diseases (reviewed in Koopman et al. 2013, Pearce et al. 2013).