Affinage

TRMU

Mitochondrial tRNA-specific 2-thiouridylase 1 · UniProt O75648

Length
421 aa
Mass
47.7 kDa
Annotated
2026-06-10
29 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRMU (MTU1) is a mitochondrially-localized, mitochondria-specific tRNA-modifying enzyme that catalyzes 2-thiouridylation of the wobble U34 position of mitochondrial tRNALys, tRNAGlu, and tRNAGln (PMID:16513084, PMID:19732863, PMID:21890497). This modification supports mitochondrial tRNA stability and aminoacylation and is required for efficient mitochondrial translation, as shown by yeast ortholog deletion that destabilizes mitochondrial tRNAs and mRNAs and impairs aminoacylation (PMID:17706197), and by in vivo liver-specific knockout in mouse and CRISPR knockout in zebrafish that abolish 2-thiolation, impair mitochondrial translation and respiratory complex activity, and reduce ATP production (PMID:27689697, PMID:30137487). The translational requirement is tissue-selective, with the liver being most vulnerable: trmu loss in zebrafish produces the most severe tRNA conformational, stability, and aminoacylation defects in liver, manifesting as complex I deficiency and hepatic steatosis (PMID:41580081). Loss of TRMU function also elevates reactive oxygen species and triggers apoptosis in hair-cell-like cells (PMID:27405449), and underlies hearing organ defects in zebrafish (PMID:30137487). Disease-causing missense mutations act as partial loss-of-function alleles: a homozygous A10S variant reduces protein stability and 2-thiouridylation and functions as a nuclear modifier that aggravates the deafness-associated 12S rRNA m.1555A>G mutation (PMID:16826519, PMID:28049726), while a broader set of pathological mutations are subject to accelerated proteolysis through direct interaction with the mitochondrial chaperone CLPX followed by degradation by the CLPP peptidase—CLPP knockdown restores mutant protein levels and tRNA 2-thiolation (PMID:38113276). TRMU mutations cause acute infantile liver failure with combined respiratory chain deficiency (PMID:19732863).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2006 High

    Establishing where TRMU acts and that its loss perturbs the mitochondrial translation apparatus, defining it as a mitochondrial tRNA-modifying enzyme and a disease modifier.

    Evidence GFP-fusion immunofluorescence in mouse and human cells plus genotyping and functional tRNA/protein-synthesis analysis of an A10S modifier of m.1555A>G deafness in patient cells

    PMID:14746906 PMID:16513084 PMID:16826519

    Open questions at the time
    • Did not define the precise chemical modification catalyzed
    • Mechanism by which A10S reduces tRNA levels not resolved at the protein-stability level
  2. 2009 High

    Identifying the enzymatic product and a primary disease phenotype, defining TRMU as the mitochondrial 2-thiouridylase whose deficiency causes infantile liver failure.

    Evidence Homozygosity mapping, mutation identification, and biochemical measurement of 2-thiouridylation in patient tissues

    PMID:19732863

    Open questions at the time
    • Did not establish the in vivo translational consequences of reduced 2-thiolation
    • Tissue specificity of liver vulnerability not mechanistically explained
  3. 2007 High

    Resolving whether the modification is required for tRNA integrity, showing that the yeast ortholog is needed for mitochondrial tRNA/mRNA stability and aminoacylation.

    Evidence Northern blots and aminoacylation assays in mto2-null S. cerevisiae

    PMID:17706197

    Open questions at the time
    • Yeast ortholog substrate set may differ from human
    • Did not address respiratory phenotype severity in vertebrate tissues
  4. 2011 High

    Testing whether 2-thiolation is strictly required for translation in human cells, finding the function dispensable under normal steady-state tRNA levels with only a Complex II assembly intermediate accumulating.

    Evidence siRNA knockdown, immunoblotting, mitochondrial translation and respiratory chain assays in patient fibroblasts and HEK293 cells

    PMID:21890497

    Open questions at the time
    • Contradicted by in vivo knockout phenotypes, leaving context-dependence unresolved
    • Did not test conditions of tRNA scarcity or tissue stress
  5. 2016 High

    Demonstrating in vivo that 2-thiolation is indispensable for mitochondrial translation, resolving the earlier dispensability ambiguity in the liver.

    Evidence Liver-specific Mtu1 knockout mice with mass spectrometry of tRNA modifications, translation and respiratory assays, and electron microscopy

    PMID:27689697

    Open questions at the time
    • Why liver is preferentially affected not mechanistically resolved
    • Did not address non-hepatic tissues
  6. 2016 Medium

    Linking TRMU loss to oxidative stress and cell death in a hearing-relevant cell type, connecting the modification defect to ROS-driven apoptosis.

    Evidence siRNA knockdown in HEI-OC-1 hair-cell-like cells with ROS, mitochondrial function, apoptosis assays, and N-acetylcysteine rescue

    PMID:27405449

    Open questions at the time
    • Single cell line, not in vivo
    • Causal chain from tRNA modification loss to ROS not fully delineated
  7. 2017 High

    Defining the molecular basis of the A10S modifier allele as a protein-destabilizing mutation in the catalytic domain that lowers 2-thiouridylation.

    Evidence Molecular dynamics, thermal shift, Western blotting, 2-thiouridine and aminoacylation assays, respiration measurements

    PMID:28049726

    Open questions at the time
    • No experimental crystal structure of the enzyme
    • Mild increase in aminoacylation efficiency unexplained mechanistically
  8. 2017 Medium

    Showing TRMU is a regulated node in mitochondrial retrograde signaling, with ROS/Ca2+-induced microRNAs tuning its expression in response to OXPHOS dysfunction.

    Evidence Cybrid models with miRNA expression analysis, antagonist transfection, and OXPHOS measurements

    PMID:28740091

    Open questions at the time
    • Specific miRNAs and direct targeting not fully validated
    • Physiological relevance beyond cybrid models unclear
  9. 2018 High

    Establishing the vertebrate phenotypic spectrum in vivo, linking 2-thiolation loss to hearing organ defects.

    Evidence CRISPR/Cas9 mtu1 knockout zebrafish with mass spectrometry, Northern blot, translation and respiratory assays, behavioral and histological analysis of auditory/vestibular organs

    PMID:30137487

    Open questions at the time
    • Cell-type basis of hair cell vulnerability not isolated
    • Did not address tissue-specific severity differences
  10. 2021 Medium

    Extending the functional reach of TRMU to skeletal biology, showing its deficiency impairs osteogenic differentiation via mitochondrial energy failure.

    Evidence Mtu1 knockdown in bone marrow MSCs with tRNA modification, respiratory and ATP assays, osteogenic differentiation, and a mouse osteopenia phenotype

    PMID:33431792

    Open questions at the time
    • Single lab, partial in vivo characterization
    • Link between ATP reduction and differentiation block not mechanistically detailed
  11. 2024 High

    Resolving how missense mutations cause partial loss-of-function, identifying a CLPX-dependent recognition and CLPP-mediated degradation pathway whose inhibition rescues mutant protein and tRNA modification.

    Evidence In vitro analysis of 17 disease mutations, immunoblotting, CLPP knockdown, CLPX co-interaction studies, 2-thiolation measurement, and molecular dynamics

    PMID:38113276

    Open questions at the time
    • Structural basis of CLPX recognition of mutant TRMU unknown
    • Therapeutic feasibility of CLPP modulation untested in vivo
  12. 2025 Medium

    Implicating TRMU in cancer drug resistance, showing its modification activity sustains OXPHOS and vemurafenib resistance in melanoma.

    Evidence Epitranscriptomic proteomics, TRMU genetic depletion in resistant cells, OXPHOS and drug-sensitivity assays

    PMID:41213009

    Open questions at the time
    • Single resistant cell line, single study
    • Mechanism linking modification to resistance metabolism not fully resolved
  13. 2026 High

    Explaining the longstanding liver-preferential vulnerability by showing tissue-specific failures in tRNA conformation, stability, and aminoacylation, with liver-preferential complex I electron flow driving hepatic complex I deficiency.

    Evidence trmu knockout zebrafish with cross-tissue mass spectrometry, tRNA conformation/stability/aminoacylation assays, respiratory complex assembly/activity assays, and histopathology

    PMID:41580081

    Open questions at the time
    • Molecular determinant of tissue-specific tRNA vulnerability not identified
    • Whether human tissue specificity follows the same logic untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How residual 2-thiolation levels quantitatively dictate clinical severity across tissues, and whether CLPP-pathway or chemical interventions can restore mutant TRMU function therapeutically, remains open.
  • No high-resolution structure of human TRMU or its substrate complex
  • Tissue-specific severity determinants not molecularly defined
  • Therapeutic modulation of CLPP-mediated degradation untested in animals

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 5 GO:0003723 RNA binding 3 GO:0016740 transferase activity 1
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 2
Partners
CLPPCLPX

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Mouse TRMU protein localizes to mitochondria, as demonstrated by immunofluorescence of NIH3T3 cells expressing TRMU-GFP fusion protein, establishing it as a mitochondrial tRNA-modifying enzyme homologous to bacterial TrmU. Immunofluorescence microscopy of TRMU-GFP fusion protein in NIH3T3 cells Biochimica et biophysica acta Medium 14746906
2006 Human TRMU protein localizes to mitochondria, demonstrated by immunofluorescence of human 143B cells expressing TRMU-GFP fusion protein. Immunofluorescence microscopy of TRMU-GFP fusion protein in human 143B cells Biochemical and biophysical research communications Medium 16513084
2006 A homozygous missense mutation (A10S) in TRMU reduces steady-state levels of mitochondrial tRNAs and impairs mitochondrial protein synthesis, acting as a nuclear modifier that aggravates mitochondrial dysfunction associated with the 12S rRNA A1555G mutation to cause deafness. The A10S mutation does not affect mitochondrial import of TRMU. Genotyping, functional analysis of mitochondrial tRNA levels and protein synthesis in patient-derived cells, import assay American journal of human genetics High 16826519
2007 In yeast S. cerevisiae, deletion of MTO2 (the yeast ortholog of TRMU) causes marked decreases in steady-state levels of mitochondrial tRNAs (tRNALys, tRNAGlu, tRNAGln, tRNALeu, tRNAGly, tRNAMet), impairs aminoacylation of tRNALys and tRNALeu, and reduces steady-state levels of mitochondrial mRNAs (CYTB, COX1, COX2, COX3, ATP6), demonstrating that tRNA modification by MTO2 is required for mitochondrial RNA stability. Northern blot analysis of mitochondrial tRNA and mRNA levels; aminoacylation assays in mto2 null yeast strains FEBS letters High 17706197
2009 TRMU encodes a mitochondria-specific tRNA-modifying enzyme (tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase) responsible for 2-thiouridylation of mitochondrial tRNAs; mutations in TRMU cause markedly reduced 2-thiouridylation levels of mitochondrial tRNAs and result in acute infantile liver failure with combined respiratory chain deficiency without mtDNA depletion. Homozygosity mapping, mutation identification, biochemical measurement of 2-thiouridylation levels in patient tissues American journal of human genetics High 19732863
2011 Loss of MTU1 (TRMU) in patient fibroblasts and HEK293 cells severely reduces 2-thiolation of mitochondrial tRNALys, tRNAGlu, and tRNAGln but does not impair overall mitochondrial translation at normal steady-state tRNA levels, indicating the 2-thiouridylase function is dispensable for translation under these conditions. The only respiratory chain abnormality observed was accumulation of a Complex II assembly intermediate without affecting fully assembled enzyme levels. Immunoblotting, siRNA knockdown, analysis of mitochondrial translation, respiratory chain enzyme assays in patient fibroblasts and HEK293 cells Human molecular genetics High 21890497
2013 In yeast, deletion of the nuclear modifier gene MTO2 suppresses aminoglycoside-sensitivity of mitochondrial 15S rRNA C1477G mutation; the double mutant (mto2/C1477G) shows decreased oxygen consumption but compensates through upregulation of glycolytic genes (HXK2, PFK1, PYK1), providing energy via glycolysis. Genetic epistasis analysis, oxygen consumption measurements, gene expression analysis, glycolytic inhibitor treatment in S. cerevisiae PloS one Medium 24339937
2016 Liver-specific knockout of Mtu1 in mice causes loss of 2-thiolation in mitochondrial tRNAs, leading to marked impairment of mitochondrial translation, disruption of mitochondrial membrane integrity, and broad decrease in respiratory complex activities in hepatocytes, demonstrating that Mtu1-dependent 2-thiolation of mt-tRNA is indispensable for mitochondrial translation in vivo. Liver-specific Mtu1 knockout mouse model, mass spectrometry of tRNA modifications, mitochondrial translation assay, respiratory complex activity assays, electron microscopy PLoS genetics High 27689697
2016 Reduced TRMU expression in HEI-OC-1 hair-cell-like cells increases mitochondrial dysfunction and reactive oxygen species (ROS) levels after neomycin treatment, leading to increased apoptosis; N-acetylcysteine rescued the mitochondrial dysfunction and apoptosis, indicating TRMU regulates mitochondrial function and ROS levels in this context. siRNA knockdown of TRMU in HEI-OC-1 cells, ROS measurement, mitochondrial function assays, cell viability/apoptosis assays, N-acetylcysteine rescue experiment Scientific reports Medium 27405449
2017 The TRMU A10S mutation introduces a Ser10 dynamic electrostatic interaction with Lys106 in the catalytic domain (shown by molecular dynamics simulations), reduces TRMU protein levels, reduces thermal stability of the TRMU protein, and causes marked decreases in 2-thiouridine modification of U34 of tRNALys, tRNAGlu, and tRNAGln while mildly increasing aminoacylation efficiency of tRNAs. The defective 2-thiouridine modification worsens mitochondrial translation impairment associated with m.1555A>G mutation, reducing respiratory chain activities, ATP production, and elevating ROS. Molecular dynamics simulation, Western blotting, thermal shift assay, tRNA modification analysis (2-thiouridine levels), aminoacylation assays, mitochondrial translation and respiration measurements The Journal of biological chemistry High 28049726
2017 Expression of TRMU is regulated by microRNAs induced by retrograde mitochondrial signals (ROS and Ca2+) in cybrid models of mtDNA diseases, altering the modification status of mitochondrial tRNAs as part of a cellular response to OXPHOS dysfunction. miRNA antagonist transfection improved the energetic state of mutant cybrid cells. cybrid cell models, miRNA expression analysis, miRNA antagonist transfection, OXPHOS measurements Scientific reports Medium 28740091
2018 Deletion of mtu1 in zebrafish using CRISPR/Cas9 abolishes 2-thiouridine modification of U34 of mitochondrial tRNALys, tRNAGlu, and tRNAGln, causes global decreases in mitochondrial tRNA levels, impairs mitochondrial translation and respiratory function, reduces ATP production, and results in defects in hearing organs including abnormal otolith size, reduced hair cell numbers, and reduced hair bundle densities. CRISPR/Cas9 knockout in zebrafish, mass spectrometry of tRNA modifications, Northern blot, mitochondrial translation assay, respiratory complex assays, behavioral tests (startle response, swimming), histology of auditory/vestibular organs Nucleic acids research High 30137487
2021 Mtu1 deficiency in bone marrow mesenchymal stem cells reduces 2-thiouridine modification of mitochondrial tRNAGln, tRNAGlu, and tRNALys, causing respiratory deficiencies and reduced mitochondrial ATP production, which suppresses osteogenic differentiation. Mtu1-deficient mice exhibit osteopenia. In vitro MSC culture with Mtu1 knockdown, tRNA modification analysis, respiratory chain assays, ATP measurement, osteogenic differentiation assays, mouse knockout model with bone phenotype Cell death & disease Medium 33431792
2024 Pathological missense mutations in MTU1 (TRMU) cause partial loss-of-function and lead to accelerated proteolysis of the mutant protein via direct interaction with the mitochondrial chaperone CLPX, followed by degradation by the mitochondrial caseinolytic peptidase CLPP. Knockdown of CLPP significantly increased mutant MTU1 protein levels and restored mt-tRNA 2-thiolation, demonstrating that accelerated CLPP-mediated proteolysis contributes to disease pathogenesis. In vitro assays of 17 disease mutations, immunoblotting, CLPP knockdown, co-interaction studies with CLPX, mt-tRNA 2-thiolation measurement, molecular dynamics simulations Nucleic acids research High 38113276
2025 TRMU expression is elevated in vemurafenib-resistant melanoma cells; genetic depletion of TRMU in resistant cells diminishes oxidative phosphorylation and resensitizes cells to vemurafenib, demonstrating that TRMU-mediated τm5s2U modification of mitochondrial tRNAs supports oxidative phosphorylation and contributes to drug resistance. Proteomics of epitranscriptomic RWE proteins, TRMU genetic depletion in resistant cell line, OXPHOS measurement, vemurafenib sensitivity assay Journal of proteome research Medium 41213009
2026 TRMU deficiency causes tissue-specific effects on mitochondrial tRNA conformation, stability, and aminoacylation, with liver being most vulnerable; trmu knockout zebrafish show higher severity of tRNA metabolic failures in liver compared to brain, muscle, eye, and ovum. Liver-specific complex I deficiency was linked to liver-preferential electron flow through complex I, manifesting as hepatic steatosis and enlargement. trmu knockout zebrafish, mass spectrometry of tRNA modifications across tissues, tRNA conformation/stability/aminoacylation assays per tissue, respiratory complex assembly and activity assays, histopathology The Journal of biological chemistry High 41580081

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations. American journal of human genetics 197 16826519
2009 Acute infantile liver failure due to mutations in the TRMU gene. American journal of human genetics 182 19732863
2010 Acute liver failure with subsequent cirrhosis as the primary manifestation of TRMU mutations. Journal of inherited metabolic disease 55 21153446
2016 Reduced TRMU expression increases the sensitivity of hair-cell-like HEI-OC-1 cells to neomycin damage in vitro. Scientific reports 52 27405449
2011 The 2-thiouridylase function of the human MTU1 (TRMU) enzyme is dispensable for mitochondrial translation. Human molecular genetics 48 21890497
2017 Biochemical Evidence for a Nuclear Modifier Allele (A10S) in TRMU (Methylaminomethyl-2-thiouridylate-methyltransferase) Related to Mitochondrial tRNA Modification in the Phenotypic Manifestation of Deafness-associated 12S rRNA Mutation. The Journal of biological chemistry 47 28049726
2016 Mtu1-Mediated Thiouridine Formation of Mitochondrial tRNAs Is Required for Mitochondrial Translation and Is Involved in Reversible Infantile Liver Injury. PLoS genetics 38 27689697
2013 Mitochondrial Infantile Liver Disease due to TRMU Gene Mutations: Three New Cases. JIMD reports 37 23625533
2018 Deletion of Mtu1 (Trmu) in zebrafish revealed the essential role of tRNA modification in mitochondrial biogenesis and hearing function. Nucleic acids research 33 30137487
2006 Human TRMU encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase is a putative nuclear modifier gene for the phenotypic expression of the deafness-associated 12S rRNA mutations. Biochemical and biophysical research communications 30 16513084
2021 TRMU deficiency: A broad clinical spectrum responsive to cysteine supplementation. Molecular genetics and metabolism 21 33485800
2004 Identification and characterization of mouse TRMU gene encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase. Biochimica et biophysica acta 20 14746906
2022 Genetic correction of TRMU allele restored the mitochondrial dysfunction-induced deficiencies in iPSCs-derived hair cells of hearing-impaired patients. Human molecular genetics 19 35467742
2015 Mto2 multisite phosphorylation inactivates non-spindle microtubule nucleation complexes during mitosis. Nature communications 19 26243668
2019 L-Cysteine supplementation prevents liver transplantation in a patient with TRMU deficiency. Molecular genetics and metabolism reports 15 30740308
2007 Deletion of the MTO2 gene related to tRNA modification causes a failure in mitochondrial RNA metabolism in the yeast Saccharomyces cerevisiae. FEBS letters 15 17706197
2013 Nuclear modifier MTO2 modulates the aminoglycoside-sensitivity of mitochondrial 15S rRNA C1477G mutation in Saccharomyces cerevisiae. PloS one 11 24339937
2015 Hepatic Copper Accumulation: A Novel Feature in Transient Infantile Liver Failure Due to TRMU Mutations? JIMD reports 10 25665837
2024 Pathological mutations promote proteolysis of mitochondrial tRNA-specific 2-thiouridylase 1 (MTU1) via mitochondrial caseinolytic peptidase (CLPP). Nucleic acids research 9 38113276
2021 Mtu1 defects are correlated with reduced osteogenic differentiation. Cell death & disease 9 33431792
2017 microRNA-mediated differential expression of TRMU, GTPBP3 and MTO1 in cell models of mitochondrial-DNA diseases. Scientific reports 9 28740091
2020 Leigh syndrome associated with TRMU gene mutations. Molecular genetics and metabolism reports 8 33365252
2020 Microtubule nucleation promoters Mto1 and Mto2 regulate cytokinesis in fission yeast. Molecular biology of the cell 7 32520628
2018 [TRMU MUTATIONS - REVERSIBLE INFANTILE LIVER FAILURE OR MULTISYSTEM DISORDER?]. Harefuah 6 29374875
2026 Deficient mitochondrial tRNA modifications arising from TRMU mutation led to the liver-specific failure. The Journal of biological chemistry 0 41580081
2026 Fatal Infantile Hepatic Dysfunction Associated With TRMU Gene Mutation and Aggravated by Cytomegalovirus Infection: A Unique Case. Cureus 0 41939582
2026 The endoplasmic reticulum protein Erg28 restrains Mto1-Mto2-γ-TuSC-mediated microtubule assembly. Cell reports 0 41989917
2025 TRMU Confers Resistance of Melanoma Cells to Vemurafenib through Modulating Mitochondrial Activities. Journal of proteome research 0 41213009
2022 Perioperative Management of Liver Retransplant in an Adult With a History of TRMU Alteration. Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation 0 35867014

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