Human mitochondrial translation — mt-tRNA modification, aminoacylation and Glu-tRNAGln transamidation, mitoribosome, and initiation/elongation factors

Thirteen polypeptides of the oxidative phosphorylation (OXPHOS) system — seven Complex I subunits, cytochrome b of Complex III, three Complex IV subunits and two Complex V subunits — are encoded by mitochondrial DNA and are made inside the mitochondrial matrix by a dedicated translation system whose protein components are all nuclear-encoded and imported. The system has four kinds of part. (1) The 22 mtDNA-encoded tRNAs must be post-transcriptionally modified to read the mitochondrial genetic code: the GTPBP3-MTO1 complex installs 5-taurinomethyluridine (taum5U) at the wobble position U34 of mt-tRNAs for Leu(UUR), Trp, Gln, Glu and Lys; NSUN3 methylates C34 of the single mt-tRNAMet to m5C34, which the dioxygenase ALKBH1 oxidises to 5-formylcytidine (f5C34) so that one tRNAMet can decode both AUG and AUA; and TRIT1 isopentenylates A37 (i6A37) of a subset of mt-tRNAs. (2) Nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (the *ARS2 family, e.g. DARS2) charge the tRNAs; because mitochondria lack a glutaminyl-tRNA synthetase, EARS2 first mischarges tRNAGln with glutamate and (3) the heterotrimeric glutamyl-tRNA(Gln) amidotransferase GatCAB (QRSL1/GatA, GATB, GATC) transamidates Glu-tRNAGln to Gln-tRNAGln. (4) The 55S mitoribosome — whose 28S small subunit contains, among others, uS7m (MRPS7), mS22 (MRPS22) and the pentatricopeptide-repeat protein mS39 (PTCD3) at the mRNA entry channel — translates the leaderless mt-mRNAs with the initiation factors MTIF2 and MTIF3 and the elongation factors TUFM (EF-Tu), TSFM (EF-Ts, its nucleotide exchange factor) and GFM1 (EF-G1). Because every one of the 13 products depends on the same apparatus, a lesion anywhere in it produces a combined (multi-complex) OXPHOS deficiency rather than a single-complex defect. The dismech knowledge base curates these as the combined oxidative phosphorylation deficiency series: GTPBP3 -> COXPD23 (MONDO:0014525); MTO1 -> MTO1 deficiency / COXPD10 (MONDO:0013865); NSUN3 -> COXPD48 (MONDO:0033566); TRIT1 -> COXPD35 (MONDO:0054742); GATC -> COXPD42 (MONDO:0030008); MRPS7 -> COXPD34 (MONDO:0054741), also a Perrault syndrome gene (MONDO:0017312); PTCD3 -> COXPD51 (MONDO:0033631); and TUFM -> COXPD4 (MONDO:0012534). Biallelic MRPS22 variants cause combined oxidative phosphorylation deficiency 5 (COXPD5, MIM:611719; not yet a dismech entry), with reduced 12S mt-rRNA and multiple respiratory chain deficiency; other MRPS22 missense alleles cause isolated ovarian dysgenesis 7 (MONDO:0020857), which dismech curates as a subtype of 46,XX gonadal dysgenesis (MONDO:0009299). ALKBH1 is curated in the dismech COXPD48 entry as the pathway partner of NSUN3, not as a disease gene.

MODULE:mitochondrial_translationDRAFTBiological Processmodules/mitochondrial_translation.yaml
mitochondrial translationGO:0032543
GO:0032543
mitochondrial translation
The module is grounded in mitochondrial translation (GO:0032543), the synthesis of the 13 mtDNA-encoded OXPHOS polypeptides on mitochondrial ribosomes.
Reactome:R-HSA-5368287
Mitochondrial translation
Initiation, elongation and termination steps follow the human Reactome pathway R-HSA-5368287 and its children R-HSA-5368286 (Mitochondrial translation initiation), R-HSA-5389840 (Mitochondrial translation elongation) and R-HSA-5419276 (Mitochondrial translation termination).
Reactome:R-HSA-6787450
tRNA modification in the mitochondrion
The mt-tRNA modification part (GTPBP3, MTO1, TRIT1) follows the human Reactome pathway R-HSA-6787450.
Reactome:R-HSA-379726
Mitochondrial tRNA aminoacylation
The aminoacylation part (DARS2 and the other *ARS2 synthetases) follows the human Reactome pathway R-HSA-379726.
file:human/ALKBH1/ALKBH1-ai-review.yaml
ALKBH1 gene review (human)
The f5C34 formation step on mt-tRNAMet (UniProtKB:Q13686, GO:0160290) matches the core function of the existing human ALKBH1 review, which also records its mitochondrial-matrix location and the regulation of mitochondrial translation (GO:0070129).
file:human/DARS2/DARS2-ai-review.yaml
DARS2 gene review (human)
The representative mitochondrial aminoacyl-tRNA synthetase (UniProtKB:Q6PI48, GO:0004815) matches the core function of the existing human DARS2 review.
file:human/GTPBP3/GTPBP3-ai-review.yaml
GTPBP3 gene review (human)
The GTPBP3 subunit of the GTPBP3-MTO1 taum5U34 synthase (UniProtKB:Q969Y2) matches the core function of the human GTPBP3 review: GTPase activity (GO:0003924) contributing to tRNA 5-taurinomethyluridine synthase activity (GO:0160236).
file:human/NSUN3/NSUN3-ai-review.yaml
NSUN3 gene review (human)
The NSUN3 mt-tRNAMet C34 methyltransferase (UniProtKB:Q9H649) matches the core function of the human NSUN3 review: tRNA (cytidine-N5)-methyltransferase activity (GO:0016428).
file:human/TRIT1/TRIT1-ai-review.yaml
TRIT1 gene review (human)
The TRIT1 tRNA A37 dimethylallyltransferase (UniProtKB:Q9H3H1) matches the core function of the human TRIT1 review: tRNA dimethylallyltransferase activity (GO:0052381).
file:human/GATC/GATC-ai-review.yaml
GATC gene review (human)
The GATC small subunit of GatCAB (UniProtKB:O43716) matches the core function of the human GATC review: a contribution to glutaminyl-tRNA synthase (glutamine-hydrolyzing) activity (GO:0050567) within the GatCAB complex (GO:0030956).
file:human/MRPS7/MRPS7-ai-review.yaml
MRPS7 gene review (human)
The MRPS7 (uS7m) small-subunit mitoribosomal protein (UniProtKB:Q9Y2R9) matches the core function of the human MRPS7 review: structural constituent of ribosome (GO:0003735) and rRNA binding (GO:0019843).
file:human/PTCD3/PTCD3-ai-review.yaml
PTCD3 gene review (human)
The PTCD3 (mS39) small-subunit mitoribosomal protein (UniProtKB:Q96EY7) matches the core function of the human PTCD3 review: structural constituent of ribosome (GO:0003735) and rRNA binding (GO:0019843).
file:human/MTO1/MTO1-ai-review.yaml
MTO1 gene review (human)
The MTO1 FAD-dependent subunit of the GTPBP3-MTO1 taum5U34 synthase (UniProtKB:Q9Y2Z2) matches the core function of the human MTO1 review: a contribution to tRNA 5-taurinomethyluridine synthase activity (GO:0160236) within the GTPBP3-MTO1 complex (GO:7770010).
file:human/QRSL1/QRSL1-ai-review.yaml
QRSL1 gene review (human)
The QRSL1 GatA glutaminase subunit of GatCAB (UniProtKB:Q9H0R6) matches the core function of the human QRSL1 review: a contribution to glutaminyl-tRNA synthase (glutamine-hydrolyzing) activity (GO:0050567) within the GatCAB complex (GO:0030956).
file:human/GATB/GATB-ai-review.yaml
GATB gene review (human)
The GATB GatB subunit of GatCAB (UniProtKB:O75879) matches the core function of the human GATB review: a contribution to glutaminyl-tRNA synthase (glutamine-hydrolyzing) activity (GO:0050567) within the GatCAB complex (GO:0030956).
file:human/MRPS22/MRPS22-ai-review.yaml
MRPS22 gene review (human)
The MRPS22 (mS22) small-subunit mitoribosomal protein (UniProtKB:P82650) matches the core function of the human MRPS22 review: structural constituent of ribosome (GO:0003735) in the mitochondrial small ribosomal subunit (GO:0005763).
file:human/MTIF2/MTIF2-ai-review.yaml
MTIF2 gene review (human)
The MTIF2 (IF2mt) initiation factor (UniProtKB:P46199) matches the core function of the human MTIF2 review: translation initiation factor activity (GO:0003743) and GTPase activity (GO:0003924) in mitochondrial translational initiation (GO:0070124).
file:human/MTIF3/MTIF3-ai-review.yaml
MTIF3 gene review (human)
The MTIF3 (IF3mt) initiation factor (UniProtKB:Q9H2K0) matches the core function of the human MTIF3 review: translation initiation factor activity (GO:0003743) in mitochondrial translational initiation (GO:0070124).
file:human/TUFM/TUFM-ai-review.yaml
TUFM gene review (human)
The TUFM (EF-Tu mt) elongation factor (UniProtKB:P49411) matches the core function of the human TUFM review: translation elongation factor activity (GO:0003746) and GTPase activity (GO:0003924) in mitochondrial translational elongation (GO:0070125).
file:human/TSFM/TSFM-ai-review.yaml
TSFM gene review (human)
The TSFM (EF-Ts mt) nucleotide exchange factor (UniProtKB:P43897) matches the core function of the human TSFM review: guanyl-nucleotide exchange factor activity (GO:0005085) in mitochondrial translational elongation (GO:0070125).
file:human/GFM1/GFM1-ai-review.yaml
GFM1 gene review (human)
The GFM1 (EF-G1mt) translocase (UniProtKB:Q96RP9) matches the core function of the human GFM1 review: translation elongation factor activity (GO:0003746) and GTPase activity (GO:0003924) in mitochondrial translational elongation (GO:0070125).
PMID:27497299
NSUN3 and ABH1 modify the wobble position of mt-tRNAMet to expand codon recognition in mitochondrial translation.
Establishes the two-step NSUN3 (m5C34) then ALKBH1/ABH1 (f5C34) modification of mt-tRNAMet.
PMID:25434004
Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy.
GTPBP3 loss causes a mitochondrial translation defect (COXPD23).
PMID:24901367
Defective i6A37 modification of mitochondrial and cytosolic tRNAs results from pathogenic mutations in TRIT1 and its substrate tRNA.
TRIT1 installs i6A37 on mitochondrial and cytosolic tRNAs; its loss causes COXPD35.
PMID:24579914
Glutamyl-tRNAGln amidotransferase is essential for mammalian mitochondrial translation in vivo.
GatCAB-dependent transamidation is the sole route to Gln-mt-tRNAGln and is required for mitochondrial translation.
PMID:30283131
Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder.
Biallelic variants in GatCAB subunits (including GATC) cause a lethal mitochondrial cardiomyopathy (COXPD42 for GATC).
PMID:25556185
Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia.
An MRPS7 (uS7m) small-subunit mitoribosomal protein variant impairs mitochondrial translation (COXPD34).
PMID:30607703
Mitochondrial ribosomal protein PTCD3 mutations cause oxidative phosphorylation defects with Leigh syndrome.
PTCD3 (mS39) variants cause a combined OXPHOS defect with Leigh syndrome (COXPD51).
PMID:17160893
Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu.
Mutations in the elongation factors GFM1 (EF-G1) and TUFM (EF-Tu) cause defective mitochondrial translation (TUFM -> COXPD4).
7Nodes
6Parts
0Variant Sets
0Variants
15Annotons
8Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:mitochondrial_translation deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Reaction chaining (advisory)

✓ every PRECEDES step chains, or its break is acknowledged via chaining_status.

  • mt_translation_initiation → mt_translation_elongation [NOT_CHECKED]
    Ordered steps of one ribonucleoprotein machine; no metabolite intermediate is passed.

Function consistency and core coverage

14 gene-function check(s) reflected in core functions · 0 conflict(s) · 1 evidence or coverage gap(s) (17 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
gtpbp3_mto1_taum5u PROTEIN_COMPLEX
Gene 		tRNA 5-taurinomethyluridine synthase activity
GO:0160236 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
gtpbp3_mto1_taum5u/gtpbp3_unit GTPBP3
UniProtKB:Q969Y2
Complex Unit 		GTPase activity
GO:0003924 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nsun3_m5c34 NSUN3
UniProtKB:Q9H649
Gene 		tRNA (cytidine-N5)-methyltransferase activity
GO:0016428 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
alkbh1_f5c34 ALKBH1
UniProtKB:Q13686
Gene 		2-oxoglutarate-dependent tRNA 5-methylcytidine formyltransferase activity
GO:0160290 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
trit1_i6a37 TRIT1
UniProtKB:Q9H3H1
Gene 		tRNA dimethylallyltransferase activity
GO:0052381 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dars2_aspartylation DARS2
UniProtKB:Q6PI48
Gene 		aspartate-tRNA ligase activity
GO:0004815 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ears2_glu_trnagln EARS2
UniProtKB:Q5JPH6
Gene 		glutamate-tRNA(Gln) ligase activity
GO:0050561 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gatcab_amidotransferase PROTEIN_COMPLEX
Gene 		glutaminyl-tRNA synthase (glutamine-hydrolyzing) activity
GO:0050567 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
gatcab_amidotransferase/qrsl1_unit QRSL1
UniProtKB:Q9H0R6
Complex Unit 		glutaminase activity
GO:0004359 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
mrps7_us7m MRPS7
UniProtKB:Q9Y2R9
Gene 		structural constituent of ribosome
GO:0003735 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mrps22_ms22 MRPS22
UniProtKB:P82650
Gene 		structural constituent of ribosome
GO:0003735 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ptcd3_ms39 PTCD3
UniProtKB:Q96EY7
Gene 		rRNA binding
GO:0019843 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mtif2_if2 MTIF2
UniProtKB:P46199
Gene 		translation initiation factor activity
GO:0003743 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mtif3_if3 MTIF3
UniProtKB:Q9H2K0
Gene 		translation initiation factor activity
GO:0003743 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tufm_eftu TUFM
UniProtKB:P49411
Gene 		translation elongation factor activity
GO:0003746 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tsfm_efts TSFM
UniProtKB:P43897
Gene 		guanyl-nucleotide exchange factor activity
GO:0005085 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gfm1_efg1 GFM1
UniProtKB:Q96RP9
Gene 		translation elongation factor activity
GO:0003746 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).

Gene-review completeness (18/18 grounded genes reviewed)

15 complete review(s) · 16 with deep research · 0 missing review · 2 reviewed but lacking deep research

Gene Review Complete Deep research
ALKBH1 Q13686 ✓ ✓ ✗
DARS2 Q6PI48 ✓ 53/54 ✓
EARS2 Q5JPH6 ✓ 21/22 ✗
GATB O75879 ✓ ✓ ✓
GATC O43716 ✓ ✓ ✓
GFM1 Q96RP9 ✓ ✓ ✓
GTPBP3 Q969Y2 ✓ ✓ ✓
MRPS22 P82650 ✓ ✓ ✓
MRPS7 Q9Y2R9 ✓ ✓ ✓
MTIF2 P46199 ✓ 21/22 ✓
MTIF3 Q9H2K0 ✓ ✓ ✓
MTO1 Q9Y2Z2 ✓ ✓ ✓
NSUN3 Q9H649 ✓ ✓ ✓
PTCD3 Q96EY7 ✓ ✓ ✓
QRSL1 Q9H0R6 ✓ ✓ ✓
TRIT1 Q9H3H1 ✓ ✓ ✓
TSFM P43897 ✓ ✓ ✓
TUFM P49411 ✓ ✓ ✓

Details

Context
mitochondrial matrixGO:0005759
Mitochondrial translation (mtDNA-encoded OXPHOS polypeptide synthesis)Biological Processmitochondrial_translation
mitochondrial translationGO:0032543
Context
mitochondrial matrixGO:0005759

Human mitochondrial translation, the machinery making the 13 mtDNA-encoded OXPHOS polypeptides. Participants are grounded to human UniProtKB accessions retrieved from the UniProt REST API (reviewed entries, organism 9606): GTPBP3 Q969Y2, MTO1 Q9Y2Z2, NSUN3 Q9H649, ALKBH1 Q13686, TRIT1 Q9H3H1, DARS2 Q6PI48, EARS2 Q5JPH6, QRSL1 Q9H0R6, GATB O75879, GATC O43716, MRPS7 Q9Y2R9, MRPS22 P82650, PTCD3 Q96EY7, MTIF2 P46199, MTIF3 Q9H2K0, TUFM P49411, TSFM P43897, GFM1 Q96RP9. GO molecular-function terms are taken from the UniProt GO annotation of each protein (or, for ALKBH1 and DARS2, from the core functions of the existing gene reviews) and verified against the local go.db; the GTPBP3-MTO1 complex function GO:0160236 (tRNA 5-taurinomethyluridine synthase activity) and complex term GO:7770010 were checked in go.db. Reactome pathway ids/titles were checked against the Reactome ContentService. The two-subunit complexes (GTPBP3-MTO1, GatCAB) are modelled as PROTEIN_COMPLEX participants with active units, so the complex activity is not assigned to every subunit. The *ARS2 family is represented by DARS2 plus EARS2 (whose nondiscriminating activity feeds GatCAB) rather than enumerated. The aminoacylation part overlaps MODULE:mitochondrial_trna_charging_and_initiator_formylation (modules/mitochondrial_trna_charging_and_initiator_formylation.yaml), which models AARS2, DARS2 and TARS2 charging and the initiator formylation step by methionyl-tRNA formyltransferase (MTFMT); MTFMT is therefore modelled there, not here. Not modelled in either module and candidates for extension: mt-tRNA processing (RNase P/PRORP, ELAC2, TRNT1), TRMU and TRMT5, the large subunit (MRPL genes), termination and recycling (MTRF1L, MRRF, GFM2), mRNA-specific translational activators (e.g. TACO1 for MT-CO1), and co-translational insertion (OXA1L). Disease consequences are cited with the MONDO ids used by the corresponding dismech knowledge-base entries.

Connections

EARS2-made Glu-mt-tRNAGln is the substrate GatCAB transamidates to Gln-mt-tRNAGln.
Wobble- and position-37-modified mt-tRNAs are required for accurate decoding by the elongating mitoribosome.
Charged mt-tRNAs are delivered to the A site by TUFM (EF-Tu).
Gln-mt-tRNAGln supplies glutamine for decoding CAA/CAG codons.
f5C34-modified mt-tRNAMet is the initiator tRNA (after formylation) that reads AUG and AUA.
The small subunit binds the leaderless mt-mRNA and the initiation factors.
The assembled 55S initiation complex enters elongation.
Part 1: mt-tRNA anticodon-loop modification
Wobble (position 34) and position-37 modification of mt-tRNAsBiological Processmt_trna_modification
mitochondrial tRNA modificationGO:0070900

Annotons

GTPBP3-MTO1: 5-taurinomethyluridine (taum5U34) synthesis
gtpbp3_mto1_taum5u
Participant: Protein Complex: GTPBP3-MTO1 complex
Protein Complex:
GTPBP3-MTO1 complexGO:7770010
Active units:
GTPBP3 GTPase subunit
Participant: Gene Product: GTPBP3
Gene Product:
GTPBP3UniProtKB:Q969Y2
Role: MnmE-family GTPase that binds the methylene-tetrahydrofolate donor; GTP hydrolysis drives the taurinomethylation reaction with MTO1.
Function:
GTPase activityGO:0003924
MTO1 FAD-binding subunit
Participant: Gene Product: MTO1
Gene Product:
MTO1UniProtKB:Q9Y2Z2
Role: MnmG-family subunit that carries the FAD cofactor of the complex and, with GTPBP3, transfers the taurinomethyl group (from taurine and 5,10-methylene-tetrahydrofolate) to U34. Its contribution is part of the complex activity (GO:0160236) rather than a separate catalytic activity, so no subunit-level function is asserted; FAD binding is a cofactor property, not the subunit's role.

Function

tRNA 5-taurinomethyluridine synthase activityGO:0160236
Substrates: uridine-34 in mt-tRNA Leu(UUR), Trp, Gln, Glu, Lys taurine 5,10-methylene-tetrahydrofolate GTP
Products: 5-taurinomethyluridine-34 (taum5U34) in mt-tRNA

Processes

mitochondrial tRNA wobble uridine modificationGO:0070899

Locations

mitochondrionGO:0005739

Installs taum5U at the wobble position of five mt-tRNAs, required for accurate and efficient decoding of NNA/NNG codons. GTPBP3 deficiency causes COXPD23 (MONDO:0014525); MTO1 deficiency causes COXPD10, mitochondrial hypertrophic cardiomyopathy with lactic acidosis (MONDO:0013865). TRMU, which 2-thiolates the same wobble uridine (taum5s2U in tRNA Gln/Glu/Lys), is a natural extension not modelled here.

Reactome:R-HSA-6787450
Human Reactome pathway tRNA modification in the mitochondrion (GTPBP3 and MTO1 reactions).
PMID:25434004
GTPBP3 loss causes a mitochondrial translation defect (COXPD23).
PMID:29348686
MTO1 and GTPBP3 defects in the same modification pathway cause distinct metabolic reprogramming.
NSUN3: mt-tRNAMet C34 5-methylation (m5C34)
nsun3_m5c34
Participant: Gene Product: NSUN3
Gene Product:
NSUN3UniProtKB:Q9H649

Function

tRNA (cytidine-N5)-methyltransferase activityGO:0016428
Substrates: cytidine-34 in mt-tRNAMet S-adenosyl-L-methionine
Products: 5-methylcytidine-34 (m5C34) in mt-tRNAMet S-adenosyl-L-homocysteine

Processes

tRNA wobble base cytosine methylationGO:0002127

Locations

mitochondrial matrixGO:0005759

First step of f5C34 formation on the single mt-tRNAMet that serves both initiation and elongation. Biallelic NSUN3 variants cause COXPD48 (MONDO:0033566).

PMID:27497299
NSUN3 deposits m5C34 on mt-tRNAMet as the substrate for ABH1 oxidation.
ALKBH1: oxidation of m5C34 to f5C34 in mt-tRNAMet
alkbh1_f5c34
Participant: Gene Product: ALKBH1
Gene Product:
ALKBH1UniProtKB:Q13686

Function

2-oxoglutarate-dependent tRNA 5-methylcytidine formyltransferase activityGO:0160290
Substrates: 5-methylcytidine-34 (m5C34) in mt-tRNAMet 2-oxoglutarate O2
Products: 5-formylcytidine-34 (f5C34) in mt-tRNAMet succinate CO2

Processes

tRNA wobble cytosine modificationGO:0002101

Locations

mitochondrial matrixGO:0005759

Fe(II)/2-oxoglutarate dioxygenase completing f5C34, which lets mt-tRNAMet read AUA as well as AUG. ALKBH1 has a broader substrate range (nuclear/cytosolic RNA and DNA demethylation) and no reported COXPD48 patient variant; dismech lists it in the COXPD48 entry as the pathway partner of NSUN3 only.

file:human/ALKBH1/ALKBH1-ai-review.yaml
Core function GO:0160290 in the mitochondrial matrix (human ALKBH1 review).
PMID:27497299
ALKBH1/ABH1 oxidises NSUN3-deposited m5C34 of mt-tRNAMet to f5C34.
TRIT1: N6-isopentenylation of A37 (i6A37)
trit1_i6a37
Participant: Gene Product: TRIT1
Gene Product:
TRIT1UniProtKB:Q9H3H1

Function

tRNA dimethylallyltransferase activityGO:0052381
Substrates: adenosine-37 in tRNA dimethylallyl diphosphate
Products: N6-dimethylallyladenosine-37 (i6A37) in tRNA diphosphate

Processes

mitochondrial tRNA modificationGO:0070900

Locations

mitochondrial matrixGO:0005759

Modifies A37 adjacent to the anticodon of a subset of mt-tRNAs (and cytosolic tRNAs, including tRNA[Ser]Sec), stabilising codon-anticodon pairing. Biallelic TRIT1 variants cause COXPD35 (MONDO:0054742).

PMID:24901367
TRIT1 pathogenic variants abolish i6A37 on mitochondrial and cytosolic tRNAs.
Reactome:R-HSA-6787450
Human Reactome pathway tRNA modification in the mitochondrion (TRIT1 reaction).

Connections

NSUN3-deposited m5C34 is the substrate ALKBH1 oxidises to f5C34.
Part 2: mt-tRNA aminoacylation
Charging of mt-tRNAs by mitochondrial aminoacyl-tRNA synthetases (*ARS2)Biological Processmt_trna_aminoacylation
tRNA aminoacylation for mitochondrial protein translationGO:0070127

Annotons

DARS2: mitochondrial aspartyl-tRNA synthetase (representative *ARS2)
dars2_aspartylation
Participant: Gene Product: DARS2
Gene Product:
DARS2UniProtKB:Q6PI48

Function

aspartate-tRNA ligase activityGO:0004815
Substrates: L-aspartate mt-tRNAAsp ATP
Products: L-aspartyl-mt-tRNAAsp AMP diphosphate

Locations

mitochondrial matrixGO:0005759

Representative of the ~19 nuclear-encoded mitochondrial aminoacyl-tRNA synthetases. DARS2 deficiency causes leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL); dismech also curates DARS2 as an axonal Charcot-Marie-Tooth type 2 gene (MONDO:0018993).

file:human/DARS2/DARS2-ai-review.yaml
Core function GO:0004815 in the mitochondrial matrix (human DARS2 review).
Reactome:R-HSA-379726
Human Reactome pathway Mitochondrial tRNA aminoacylation.
EARS2: nondiscriminating glutamyl-tRNA synthetase (Glu-tRNAGln formation)
ears2_glu_trnagln
Participant: Gene Product: EARS2
Gene Product:
EARS2UniProtKB:Q5JPH6

Function

glutamate-tRNA(Gln) ligase activityGO:0050561
Substrates: L-glutamate mt-tRNAGln (and mt-tRNAGlu) ATP
Products: L-glutamyl-mt-tRNAGln (misacylated) AMP diphosphate

Locations

mitochondrial matrixGO:0005759

Charges both mt-tRNAGlu and mt-tRNAGln with glutamate; the misacylated Glu-tRNAGln is the substrate of GatCAB because mitochondria have no glutaminyl-tRNA synthetase.

Part 3: Glu-tRNAGln to Gln-tRNAGln transamidation
GatCAB transamidation of Glu-mt-tRNAGlnReactiongln_trna_transamidation
glutaminyl-tRNAGln biosynthesis via transamidationGO:0019988

Annotons

GatCAB: glutamyl-tRNA(Gln) amidotransferase
gatcab_amidotransferase
Participant: Protein Complex: glutamyl-tRNA(Gln) amidotransferase complex (GatCAB)
Protein Complex:
glutamyl-tRNA(Gln) amidotransferase complex (GatCAB)GO:0030956
Active units:
QRSL1 (GatA) glutaminase subunit
Participant: Gene Product: QRSL1
Gene Product:
QRSL1UniProtKB:Q9H0R6
Role: Hydrolyses glutamine to release the ammonia used as amide donor.
Function:
glutaminase activityGO:0004359
GATB (GatB) kinase/transamidase subunit
Participant: Gene Product: GATB
Gene Product:
GATBUniProtKB:O75879
Role: Phosphorylates the Glu side chain of Glu-tRNAGln and transfers ammonia channelled from GatA to form Gln-tRNAGln.
GATC (GatC) small subunit
Participant: Gene Product: GATC
Gene Product:
GATCUniProtKB:O43716
Role: Small subunit required for GatA/GatB assembly and stability of the heterotrimer.

Function

glutaminyl-tRNA synthase (glutamine-hydrolyzing) activityGO:0050567
Substrates: L-glutamyl-mt-tRNAGln L-glutamine ATP
Products: L-glutaminyl-mt-tRNAGln L-glutamate ADP phosphate

Locations

mitochondrionGO:0005739

Sole route to Gln-mt-tRNAGln, so its loss affects all 13 mtDNA-encoded products. Biallelic GATC variants cause COXPD42, a lethal infantile mitochondrial cardiomyopathy (MONDO:0030008); QRSL1 and GATB variants cause the same disorder class (not yet curated in dismech).

PMID:24579914
GatCAB is essential for mammalian mitochondrial translation in vivo.
PMID:30283131
Pathogenic variants in GatCAB subunits cause a lethal mitochondrial cardiomyopathy.
Part 4: mitoribosome small subunit (mRNA binding and decoding)
28S mitoribosomal small subunitProtein Complexmitoribosome_ssu
mitochondrial small ribosomal subunitGO:0005763

Annotons

MRPS7 (uS7m): small-subunit ribosomal protein
mrps7_us7m
Participant: Gene Product: MRPS7
Gene Product:
MRPS7UniProtKB:Q9Y2R9

Function

structural constituent of ribosomeGO:0003735

Locations

mitochondrial inner membraneGO:0005743

Conserved uS7-family 12S rRNA-binding protein required for assembly of the small subunit. Biallelic MRPS7 variants cause COXPD34 (MONDO:0054741) and are also reported in Perrault syndrome (MONDO:0017312) and syndromic premature ovarian insufficiency.

PMID:25556185
MRPS7 is a 12S rRNA-binding subunit required for small-subunit assembly; a homozygous variant impairs mitochondrial protein synthesis (COXPD34).
MRPS22 (mS22): small-subunit ribosomal protein
mrps22_ms22
Participant: Gene Product: MRPS22
Gene Product:
MRPS22UniProtKB:P82650

Function

structural constituent of ribosomeGO:0003735

Locations

mitochondrial inner membraneGO:0005743

Mitochondria-specific small-subunit protein. MRPS22 variants cause combined OXPHOS deficiency and, as curated in dismech, 46,XX gonadal dysgenesis (MONDO:0009299).

PTCD3 (mS39): pentatricopeptide-repeat protein of the mRNA entry channel
ptcd3_ms39
Participant: Gene Product: PTCD3
Gene Product:
PTCD3UniProtKB:Q96EY7

Function

rRNA bindingGO:0019843

Locations

mitochondrial inner membraneGO:0005743

Integral PPR protein of the small subunit forming part of the mRNA entry channel that receives leaderless mt-mRNAs. Biallelic PTCD3 variants cause COXPD51 with Leigh syndrome (MONDO:0033631).

PMID:30607703
PTCD3 variants cause OXPHOS defects with Leigh syndrome (COXPD51).
Part 5: translation initiation
Initiation on leaderless mt-mRNA (MTIF2, MTIF3)Biological Processmt_translation_initiation
mitochondrial translational initiationGO:0070124
Reactome:R-HSA-5368286
Human Reactome pathway Mitochondrial translation initiation (MTIF2, MTIF3).

Annotons

MTIF2: initiation factor IF-2mt
mtif2_if2
Participant: Gene Product: MTIF2
Gene Product:
MTIF2UniProtKB:P46199

Function

translation initiation factor activityGO:0003743

Locations

mitochondrial matrixGO:0005759

GTPase that delivers formyl-Met-tRNAMet (decoding AUG/AUA via f5C34) to the start codon on the small subunit.

MTIF3: initiation factor IF-3mt
mtif3_if3
Participant: Gene Product: MTIF3
Gene Product:
MTIF3UniProtKB:Q9H2K0

Function

translation initiation factor activityGO:0003743

Locations

mitochondrionGO:0005739

Dissociates the 55S monosome and proofreads start-codon selection on the small subunit.

Part 6: translation elongation
Elongation (TUFM, TSFM, GFM1)Biological Processmt_translation_elongation
mitochondrial translational elongationGO:0070125
Reactome:R-HSA-5389840
Human Reactome pathway Mitochondrial translation elongation (TUFM, TSFM, GFM1).

Annotons

TUFM: elongation factor EF-Tu (aminoacyl-tRNA delivery)
tufm_eftu
Participant: Gene Product: TUFM
Gene Product:
TUFMUniProtKB:P49411

Function

translation elongation factor activityGO:0003746

Locations

mitochondrial matrixGO:0005759

GTP-bound EF-Tu delivers the modified, charged mt-tRNAs to the ribosomal A site. TUFM deficiency causes COXPD4 (MONDO:0012534).

PMID:17160893
TUFM (EFTu) mutation causes infantile encephalopathy with defective mtDNA translation.
TSFM: elongation factor EF-Ts (EF-Tu nucleotide exchange)
tsfm_efts
Participant: Gene Product: TSFM
Gene Product:
TSFMUniProtKB:P43897

Function

guanyl-nucleotide exchange factor activityGO:0005085

Locations

mitochondrial matrixGO:0005759

Recycles EF-Tu-GDP to EF-Tu-GTP for the next delivery cycle.

GFM1: elongation factor EF-G1 (translocation)
gfm1_efg1
Participant: Gene Product: GFM1
Gene Product:
GFM1UniProtKB:Q96RP9

Function

translation elongation factor activityGO:0003746

Locations

mitochondrial matrixGO:0005759

GTPase that translocates the peptidyl-tRNA and mRNA by one codon after peptide-bond formation.

PMID:17160893
GFM1 (EFG1) mutation causes defective mtDNA translation.