Mitochondrial translation (Homo sapiens)
From WikiPathways
Description
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). View original pathway at:Reactome.
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). View original pathway at:Reactome.
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- Agrawal RK, Sharma MR.; ''Structural aspects of mitochondrial translational apparatus.''; PubMed Europe PMC Scholia
- Nozaki Y, Matsunaga N, Ishizawa T, Ueda T, Takeuchi N.; ''HMRF1L is a human mitochondrial translation release factor involved in the decoding of the termination codons UAA and UAG.''; PubMed Europe PMC Scholia
- Cavdar Koc E, Burkhart W, Blackburn K, Moseley A, Spremulli LL.; ''The small subunit of the mammalian mitochondrial ribosome. Identification of the full complement of ribosomal proteins present.''; PubMed Europe PMC Scholia
- Akabane S, Ueda T, Nierhaus KH, Takeuchi N.; ''Ribosome rescue and translation termination at non-standard stop codons by ICT1 in mammalian mitochondria.''; PubMed Europe PMC Scholia
- Temperley R, Richter R, Dennerlein S, Lightowlers RN, Chrzanowska-Lightowlers ZM.; ''Hungry codons promote frameshifting in human mitochondrial ribosomes.''; PubMed Europe PMC Scholia
- Lind C, Sund J, Aqvist J.; ''Codon-reading specificities of mitochondrial release factors and translation termination at non-standard stop codons.''; PubMed Europe PMC Scholia
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- Chung HK, Spremulli LL.; ''Purification and characterization of elongation factor G from bovine liver mitochondria.''; PubMed Europe PMC Scholia
- Ott M, Herrmann JM.; ''Co-translational membrane insertion of mitochondrially encoded proteins.''; PubMed Europe PMC Scholia
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- Pearce S, Nezich CL, Spinazzola A.; ''Mitochondrial diseases: translation matters.''; PubMed Europe PMC Scholia
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DataNodes
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Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| 10-formyl-THF | R-HSA-5389841 (Reactome)  | |||
| 28S
ribosomal subunit:MTIF3:MTIF2:GTP:mRNA:fMet-tRNA | Arrow | R-HSA-5389849 (Reactome) | ||
| 28S
ribosomal subunit:MTIF3:MTIF2:GTP:mRNA:fMet-tRNA | R-HSA-5389839 (Reactome) | |||
| 28S
ribosomal subunit:MTIF3:MTIF2:GTP:mRNA:fMet-tRNA | mim-catalysis | R-HSA-5389839 (Reactome) | ||
| 28S ribosomal subunit:MTIF3 | Arrow | R-HSA-5368279 (Reactome) | ||
| 28S ribosomal subunit:MTIF3 | R-HSA-5389849 (Reactome) | |||
| 28S ribosomal subunit | Arrow | R-HSA-5419273 (Reactome) | ||
| 28S ribosomal subunit | R-HSA-5368279 (Reactome) | |||
| 39S ribosomal subunit | Arrow | R-HSA-5419273 (Reactome) | ||
| 39S ribosomal subunit | R-HSA-5389839 (Reactome) | |||
| 55S ribosome:MRRF:GFM2:GTP | Arrow | R-HSA-5419277 (Reactome) | ||
| 55S ribosome:MRRF:GFM2:GTP | R-HSA-5419273 (Reactome) | |||
| 55S ribosome:MRRF:GFM2:GTP | mim-catalysis | R-HSA-5419273 (Reactome) | ||
| 55S ribosome:mRNA:fMet-tRNA:aminoacyl-tRNA:TUFM:GTP | Arrow | R-HSA-5389848 (Reactome) | ||
| 55S ribosome:mRNA:fMet-tRNA:aminoacyl-tRNA:TUFM:GTP | R-HSA-5389842 (Reactome) | |||
| 55S ribosome:mRNA:fMet-tRNA:aminoacyl-tRNA:TUFM:GTP | mim-catalysis | R-HSA-5389842 (Reactome) | ||
| 55S ribosome:mRNA:fMet-tRNA:aminoacyl-tRNA | Arrow | R-HSA-5389842 (Reactome) | ||
| 55S ribosome:mRNA:fMet-tRNA:aminoacyl-tRNA | R-HSA-5389857 (Reactome) | |||
| 55S ribosome:mRNA:fMet-tRNA | Arrow | R-HSA-5389839 (Reactome) | ||
| 55S ribosome:mRNA:fMet-tRNA | R-HSA-5389848 (Reactome) | |||
| 55S ribosome:mRNA:peptidyl-tRNA at P-site | Arrow | R-HSA-5419279 (Reactome) | ||
| 55S ribosome:mRNA:peptidyl-tRNA at P-site | R-HSA-5419264 (Reactome) | |||
| 55S ribosome:mRNA:peptidyl-tRNA:MTRF1L:GTP | Arrow | R-HSA-5419264 (Reactome) | ||
| 55S ribosome:mRNA:peptidyl-tRNA:MTRF1L:GTP | R-HSA-5419271 (Reactome) | |||
| 55S ribosome:mRNA:tRNA:MRRF | Arrow | R-HSA-5419281 (Reactome) | ||
| 55S ribosome:mRNA:tRNA:MRRF | R-HSA-5419277 (Reactome) | |||
| 55S ribosome:mRNA:tRNA:peptidyl-tRNA at A-site | Arrow | R-HSA-5389857 (Reactome) | ||
| 55S ribosome:mRNA:tRNA:peptidyl-tRNA at A-site | R-HSA-5419261 (Reactome) | |||
| 55S ribosome:mRNA:tRNA:peptidyl-tRNA:GFM1:GTP | Arrow | R-HSA-5419261 (Reactome) | ||
| 55S ribosome:mRNA:tRNA:peptidyl-tRNA:GFM1:GTP | R-HSA-5419279 (Reactome) | |||
| 55S ribosome:mRNA:tRNA:peptidyl-tRNA:GFM1:GTP | mim-catalysis | R-HSA-5419279 (Reactome) | ||
| 55S ribosome:mRNA:tRNA | Arrow | R-HSA-5419271 (Reactome) | ||
| 55S ribosome:mRNA:tRNA | R-HSA-5419281 (Reactome) | |||
| GDP | Arrow | R-HSA-5389839 (Reactome) | ||
| GDP | Arrow | R-HSA-5419269 (Reactome) | ||
| GDP | Arrow | R-HSA-5419271 (Reactome) | ||
| GFM1:GDP | Arrow | R-HSA-5419279 (Reactome) | ||
| GFM1:GTP | R-HSA-5419261 (Reactome) | |||
| GFM2:GDP | Arrow | R-HSA-5419273 (Reactome) | ||
| GFM2:GTP | R-HSA-5419277 (Reactome) | |||
| GTP | R-HSA-5419264 (Reactome) | |||
| GTP | R-HSA-5419268 (Reactome) | |||
| MRRF | Arrow | R-HSA-5419273 (Reactome) | ||
| MRRF | R-HSA-5419281 (Reactome) | |||
| MTFMT | mim-catalysis | R-HSA-5389841 (Reactome) | ||
| MTIF2:GTP | R-HSA-5389849 (Reactome) | |||
| MTIF2 | Arrow | R-HSA-5389839 (Reactome) | ||
| MTIF3 | Arrow | R-HSA-5389839 (Reactome) | ||
| MTIF3 | R-HSA-5368279 (Reactome) | |||
| MTRF1L, ICT1 | Arrow | R-HSA-5419271 (Reactome) | ||
| MTRF1L, ICT1 | R-HSA-5419264 (Reactome) | |||
| Met-tRNA(Met) | R-HSA-5389841 (Reactome) | |||
| Pi | Arrow | R-HSA-5389839 (Reactome) | ||
| Pi | Arrow | R-HSA-5389842 (Reactome) | ||
| Pi | Arrow | R-HSA-5419271 (Reactome) | ||
| Pi | Arrow | R-HSA-5419273 (Reactome) | ||
| Pi | Arrow | R-HSA-5419279 (Reactome) | ||
| R-HSA-5368279 (Reactome) | As inferred from bovine mitochondrial homologs, MTIF3 (IF-3Mt, IF3mt) binds the 28S ribosomal subunit in preparation for binding mRNA and initiating translation. MTIF3 also dissociates 55S particles that have not already been dissociated by GFM2 plus MRRF and displaces N-formylmethionyl-tRNA from the 28S subunit in the absence of mRNA but cannot displace mRNA from the 28S subunit. The activity of MTIF3 is necessary for translation initiation.. The 28S subunit associates with the matrix-side face of the inner mitochondrial membrane and translation products are inserted directly into the membrane. | |||
| R-HSA-5389839 (Reactome) | As inferred from bovine homologs, the 39S ribosomal subunit binds the 28S subunit:mRNA:N-formylmethionyl-tRNA complex, MTIF2 hydrolyzes GTP, then MTIF2, GDP, and MTIF3 dissociate. (MTIF2 has a very low affinity for GDP so it is unclear whether MTIF2 and GDP remain associated after hydrolysis of GTP.) The 28S subunit, 39S subunit, and 55S holoribosome associate with the inner mitochondrial membrane during translation and in the absence of translation. | |||
| R-HSA-5389841 (Reactome) | Like bacteria, mitochondria initiate translation with N-formylmethionine. Unlike bacteria, mammalian mitochondria do not have a tRNA dedicated to N-formylmethionine. Instead, the mitochondrial enzyme MTFMT (methionyl-tRNA formyltransferase, FMT, FMT1) transfers a formyl group from 10-formyltetrahydrofolate (10-formyl-THF) to the amino group of methionyl-tRNA in a portion of the methionyl-tRNAs in the matrix. | |||
| R-HSA-5389842 (Reactome) | As inferred from bovine homologs, interaction of the cognate aminoacyl-tRNA in the A-site with the codon in the mRNA causes TUFM (EF-Tu) to hydrolyze GTP. TUFM:GDP then dissociates from the ribosome. | |||
| R-HSA-5389845 (Reactome) | As inferred from bovine homologs, TUFM:GTP (EF-Tu:GTP) binds an aminoacyl-tRNA to form the ternary complex. | |||
| R-HSA-5389848 (Reactome) | As inferred from bovine homologs, the ternary complex containing TUFM:GTP (EF-Tu:GTP) and aminoacyl-tRNA enters the A-site of the 55S ribosome (reviewed in Christian and Spremulli 2012). | |||
| R-HSA-5389849 (Reactome) | As inferred from bovine homologs, the 28S ribosomal subunit in a complex with MTIF3 (IF-3Mt, IF3mt) binds mRNA and, at some point, MTIF2:GTP (IF-2Mt:GTP, IF2mt:GTP). If an initiation codon is present at the 5' end of the mRNA then MTIF2:GTP assists the binding of N-formylmethionyl-tRNA and a stable, productive initiation complex results. If no initiation codon is present, the mRNA slides through the 28S subunit and then dissociates. | |||
| R-HSA-5389857 (Reactome) | As inferred from bovine homologs, the ribosome catalyzes formation of a peptide bond between the aminoacyl group of the aminoacyl-tRNA at the A-site and the peptidyl-tRNA at the P-site. The result is a polypeptide, longer by one amino acid, attached to the tRNA at the A-site by an ester bond. A deacylated tRNA remains at the P-site. 55S ribosomes associate with the inner mitochondrial membrane and the translation products are cotranslationally inserted into the inner membrane. | |||
| R-HSA-5419261 (Reactome) | GFMT1:GTP (EF-G1mt:GTP) binds ribosomes possessing a peptidyl-tRNA at the A site and an empty P site (Bhargava et al. 2004, Tsuboi et al. 2009, inferred from bovine homologs in Chung and Spremulli 1990). | |||
| R-HSA-5419264 (Reactome) | MTRF1L (mtRF1a) binds the stop codons UAA and UAG of the mRNA when they are in the A site of the ribosome (Soleimanpour-Lichaei 2007, Nozaki et al. 2008). (The UGA codon is recognized by the tryptophan tRNA in mitochondrial translation.) ICT1 can also bind standard stop codons in the A-site (inferred from pig mitochondrial ribosomes in Akabane et al. 2014). MTRF1 was also thought to play a role in translation termination by recognizing the unconventional termination codons AGA and AGG (Zhang and Spremulli 1998, Young et al. 2010) but frameshifting is now confirmed in the termination mechanism of these codons (Temperley et al. 2010). Structural features of MTRF1 have been reported suggesting it could recognize an empty A-site (Huynen et al. 2012) or UAA and UAG codons (Lind et al. 2013) however there is no direct experimental data to confirm these last two postulates. | |||
| R-HSA-5419268 (Reactome) | As inferred from bovine homologs, TSFM (EF-Ts, EF-TsMt) acts as a guanine nucleotide exchange factor for TUFM (EF-Tu). In the second step of the process TUFM in the TUFM:TSFM complex binds GTP and TSFM is released, yielding TUFM:GTP and TSFM. | |||
| R-HSA-5419269 (Reactome) | As inferred from bovine homologs, TSFM (EF-Ts, EF-TsMt) acts as a guanine nucleotide exchange factor to regenerate TUFM:GTP (EF-Tu:GTP) from TUFM:GDP. In the first step of the process TSFM binds TUFM:GDP and displaces GDP, yielding a TSFM:TUFM complex and GDP. | |||
| R-HSA-5419271 (Reactome) | Binding of the MTRF1L (MTRF1a) termination factor triggers hydrolysis of the peptidyl-tRNA bond by the 39S subunit of the ribosome and release of the translated polypeptide (Soleimanpour-Lichaei et al. 2007, Nozaki et al. 2008, reviewed in Christian and Spremulli 2012). MTRF1L hydrolyzes GTP during the reaction. Stalled ribosomes are rescued by binding of an ICT1 protein in addition to the ICT1 subunit integrated in the 39S subunit (Richter et al. 2010, Akabane et al. 2014). | |||
| R-HSA-5419273 (Reactome) | When complexed with ribosomes GFM2 (EF-G2mt) hydrolyzes GTP and, together with MRRF, acts as a ribosome releasing factor by splitting 55S ribosomes into 28S and 39S subunits (Tsuboi et al. 2009). Though GTP is hydrolyzed during the reaction, hydrolysis is not necessary for splitting the 55S ribosome into 39S and 28S subunits, but is necessary for dissociation of GFM2 (as GFM2:GDP) and MRRF from the large ribosomal subunit after splitting (Tsuboi et al. 2009). | |||
| R-HSA-5419277 (Reactome) | GFM2:GTP (EF-G2mt:GTP) joins MRRF at the A site of the ribosome after translation has been terminated by MTRF1L (MTRF1a) at a stop codon. | |||
| R-HSA-5419279 (Reactome) | GFM1 (EF-Gmt, EF-G1mt) of the GFM1:GTP complex hydrolyzes GTP, yielding GFM1:GDP (Tsuboi et al. 2009). The hydrolysis of GTP drives translocation of the peptidyl-tRNA from the A-site to the P-site with consequent ejection of the deacylated tRNA from the P-site and translocation of the ribosome in the 3' direction along the mRNA (Bhargava et al. 2004, Tsuboi et al. 2009, inferred from bovine homologs in Chung and Spremulli 1990). | |||
| R-HSA-5419281 (Reactome) | The mitochondrial ribosome releasing factor MRRF (RRF) binds the 55S ribosome at the A-site after translation has been terminated by MTRF1L (MTRF1a) at a stop codon and the translated polypeptide has been hydrolyzed from the last tRNA, which remains in the P-site (Rorbach et al. 2008). | |||
| THF | Arrow | R-HSA-5389841 (Reactome) | ||
| TSFM | Arrow | R-HSA-5419268 (Reactome) | ||
| TSFM | R-HSA-5419269 (Reactome) | |||
| TUFM:GDP | Arrow | R-HSA-5389842 (Reactome) | ||
| TUFM:GDP | R-HSA-5419269 (Reactome) | |||
| TUFM:GTP:aminoacyl-tRNA | Arrow | R-HSA-5389845 (Reactome) | ||
| TUFM:GTP:aminoacyl-tRNA | R-HSA-5389848 (Reactome) | |||
| TUFM:GTP | Arrow | R-HSA-5419268 (Reactome) | ||
| TUFM:GTP | R-HSA-5389845 (Reactome) | |||
| TUFM:TSFM | Arrow | R-HSA-5419269 (Reactome) | ||
| TUFM:TSFM | R-HSA-5419268 (Reactome) | |||
| aminoacyl-tRNA | R-HSA-5389845 (Reactome) | |||
| fMet-tRNA(fMet) | Arrow | R-HSA-5389841 (Reactome) | ||
| fMet-tRNA(fMet) | R-HSA-5389849 (Reactome) | |||
| mRNA | Arrow | R-HSA-5419277 (Reactome) | ||
| mRNA | R-HSA-5389849 (Reactome) | |||
| polypeptide | Arrow | R-HSA-5419271 (Reactome) | ||
| tRNA(Met) | Arrow | R-HSA-5419279 (Reactome) | ||
| tRNA | Arrow | R-HSA-5419277 (Reactome) |
