{"gene":"TRMT10C","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2021,"finding":"Cryo-EM structure of human mtRNase P bound to precursor tRNA revealed that TRMT10C (MRPP1) and SDR5C1 (MRPP2) form a subcomplex that binds conserved mitochondrial tRNA elements including the anticodon loop, and positions the tRNA for methylation; PRORP (MRPP3) is then recruited and activated through interactions with its PPR and nuclease domains to ensure precise pre-tRNA cleavage.","method":"Cryo-EM structure determination with functional validation","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure at mechanistic resolution, directly shows substrate recognition and processing mechanism with multiple orthogonal validations","pmids":["34489609"],"is_preprint":false},{"year":2018,"finding":"X-ray crystallography and SAXS analyses showed that the TRMT10C N-terminus is involved in tRNA binding and monomer-monomer self-interaction, while the C-terminal SPOUT fold contains key residues for SAM binding and N1-methylation. The entire TRMT10C interacts with MRPP2 (SDR5C1) to form the N1-methylation subcomplex, whereas the full MRPP1-MRPP2-MRPP3 RNase P complex assembles only in the presence of precursor tRNA.","method":"X-ray crystallography, SAXS, interaction assays, activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus SAXS plus functional assays in one study, single lab but multiple orthogonal methods","pmids":["29880640"],"is_preprint":false},{"year":2017,"finding":"TRMT10C (MRPP1) and SDR5C1 (MRPP2) form a tRNA-maturation platform: the MRPP1/2 subcomplex retains the tRNA product after 5'-processing by RNase P, significantly enhances efficiency of ELAC2-catalyzed 3'-processing for 17 of 22 mitochondrial tRNAs, and then presents the nascent tRNA to the mitochondrial CCA-adding enzyme.","method":"In vitro reconstitution assays with purified proteins and mitochondrial tRNA substrates","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with multiple tRNA substrates and sequential enzyme assays, single lab but multiple orthogonal functional experiments","pmids":["29040705"],"is_preprint":false},{"year":2016,"finding":"Patients with TRMT10C missense variants (p.Arg181Leu and p.Thr272Ala) showed decreased MRPP1 protein levels and increased mt-RNA precursors indicative of impaired mt-RNA processing and defective mitochondrial protein synthesis; lentiviral transduction of wild-type TRMT10C rescued mt-RNA processing and mitochondrial protein synthesis defects. The variants affect MRPP1 protein stability and mt-tRNA processing without affecting m1R9 methyltransferase activity.","method":"Patient fibroblast functional studies, lentiviral rescue, Northern blotting, mitochondrial protein synthesis assay","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional rescue experiment with wild-type TRMT10C plus multiple biochemical readouts, single lab with multiple orthogonal methods","pmids":["27132592"],"is_preprint":false},{"year":2015,"finding":"TRMT10C interacts with SDR5C1 (MRPP2/HSD10); pathogenic SDR5C1 mutations disrupt homotetramerization of SDR5C1 and/or impair its interaction with TRMT10C, leading to impaired tRNA processing and methylation activities of the mtRNase P complex.","method":"Biochemical characterization of recombinant mutant proteins, co-immunoprecipitation, enzymatic activity assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction studies plus functional methyltransferase and processing assays with disease mutants, single lab with multiple orthogonal methods","pmids":["25925575"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of the MRPP3 (PRORP) nuclease subunit showed a distorted, non-productive active site, leading to the proposed mechanism that PRORP switches to a productive state only upon association with MRPP1 (TRMT10C) and MRPP2 through an induced-fit process when pre-tRNA substrate is present.","method":"X-ray crystallography of MRPP3, structural analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure of a subunit with mechanistic interpretation, but mechanistic conclusion about TRMT10C-mediated activation is structural inference from a single lab","pmids":["25953853"],"is_preprint":false},{"year":2011,"finding":"MRPP1 (TRMT10C) is essential for mt-tRNA processing (5' end), RNA modification, translation, and mitochondrial respiration; MRPP1 and MRPP3 together process the 5' ends of tRNAs and the 5' non-tRNA-containing site of the CO1 transcript.","method":"Deep sequencing of transcript ends after siRNA knockdown, Northern blotting, mitochondrial translation assay","journal":"Cell cycle","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockdown with multiple orthogonal readouts (sequencing, Northern blot, translation, respiration), replicated across multiple studies","pmids":["21857155"],"is_preprint":false},{"year":2011,"finding":"MRPP1 (TRMT10C) is required for the processing of mitochondrial long noncoding RNAs generated from the mitochondrial genome.","method":"Deep sequencing, Northern blotting, strand-specific qRT-PCR with MRPP1 knockdown","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — knockdown with multiple readouts (sequencing, Northern blot) but single lab, single study","pmids":["22028365"],"is_preprint":false},{"year":2014,"finding":"HSD10 (SDR5C1/MRPP2) is required for maintaining normal MRPP1 (TRMT10C) protein levels; knockdown of HSD10 causes reduction in MRPP1 protein (but not MRPP3) and impairs processing of precursor tRNAs from the mitochondrial heavy strand. Ectopic expression of HSD10 restores MRPP1 levels and partially rescues RNA processing.","method":"siRNA knockdown, ectopic overexpression, Western blotting, patient fibroblast studies, RT-PCR of precursor tRNAs","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown plus rescue experiments with multiple readouts, single lab; reveals TRMT10C stability dependence on SDR5C1","pmids":["24549042"],"is_preprint":false},{"year":2019,"finding":"Purified mtRNase P (TRMT10C/MRPP1, MRPP2, MRPP3) recognizes, cleaves, and methylates a subset but not all mitochondrial pre-tRNAs in vitro; addition of SAM (the TRMT10C cofactor) enhances binding and cleavage of some mitochondrial pre-tRNAs, and the presence of MRPP3 can enhance the methylation activity of the MRPP1/2 subcomplex.","method":"In vitro cleavage and methylation assays with purified recombinant mtRNase P components","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with purified proteins, single lab, single study","pmids":["31455609"],"is_preprint":false},{"year":2023,"finding":"Kinetic analysis showed that PRORP (MRPP3) alone can bind pre-tRNAs with nanomolar affinity and cleave some at reduced efficiency without TRMT10C-SDR5C1. The main function of the TRMT10C-SDR5C1 subcomplex is to direct PRORP's nuclease domain to the correct cleavage site, increasing the rate and accuracy of cleavage, likely by compensating for structural erosion of canonical features in mitochondrial tRNAs.","method":"Kinetic analysis with purified recombinant proteins, 12 different mitochondrial pre-tRNA substrates","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative kinetics with 12 substrates, multiple protein combinations, single lab with rigorous controls","pmids":["37779095"],"is_preprint":false},{"year":2020,"finding":"Disease-linked mutations in mitochondrial pre-tRNAIle, pre-tRNALeu(UUR), and pre-tRNAMet reduce MRPP1 (TRMT10C)-catalyzed methylation activity (up to ~90% reduction) and 5' end processing by mtRNase P; several mutations weaken pre-tRNA binding affinity (2- to 6-fold higher Ks than wild-type).","method":"In vitro methylation and cleavage assays with recombinant mtRNase P and disease-mutant pre-tRNA substrates, binding assays","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with quantitative kinetics, single lab, single study","pmids":["33380464"],"is_preprint":false},{"year":2016,"finding":"In Drosophila, the MRPP1 ortholog Roswell is essential for development, localizes to mitochondria, and its loss causes defective mitochondrial tRNA processing and mitochondrial dysfunction in vivo.","method":"Homology-based identification, genetic knockdown/overexpression, immunofluorescence localization, mitochondrial tRNA processing assays, lethality assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic loss-of-function with direct tRNA processing readout in Drosophila model, corroborated by human disease data","pmids":["27131785"],"is_preprint":false},{"year":2017,"finding":"Novel HSD17B10 missense mutations (p.V12L and p.V176M) reduce dehydrogenase, methyltransferase, and tRNA processing activities of the MRPP2-TRMT10C complex; p.V12L reduces SDR5C1 stability, while p.V176M impairs kinetics and complex formation with TRMT10C.","method":"Biochemical characterization of recombinant mutant proteins, enzymatic activity assays, complex formation assays","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical assays with recombinant proteins, single lab, single study","pmids":["28888424"],"is_preprint":false},{"year":2016,"finding":"A novel HSD17B10 p.K212E mutation impairs SDR5C1-dependent mitochondrial RNase P activities (5'-processing and methylation of purine-9 of mitochondrial tRNAs), suggesting pathogenicity through general mitochondrial dysfunction caused by reduced maturation of mitochondrial tRNAs.","method":"Functional assays of mitochondrial RNase P activity in patient cells and in vitro with recombinant mutant protein","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional assays with patient mutation and recombinant protein, single lab, single study","pmids":["26950678"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of the mitochondrial RNase Z complex (ELAC2/SDR5C1/TRMT10C) bound to mitochondrial tRNAHis revealed that TRMT10C-SDR5C1 participates in the 3'-processing complex and provides the molecular rationale for the 5'-to-3' tRNA processing order in mitochondria.","method":"Cryo-EM structure determination of the ELAC2/SDR5C1/TRMT10C complex with tRNA substrate","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structures at multiple maturation states, single lab with high-resolution structural evidence","pmids":["39516281"],"is_preprint":false},{"year":2025,"finding":"TRMT10C and SDR5C1 specifically facilitate ELAC2-mediated 3'-end processing of structurally degenerate mitochondrial tRNAs lacking the canonical elbow; processing of noncanonical mt-tRNAs depends on direct protein-protein interactions between ELAC2 and TRMT10C rather than direct ELAC2-RNA contacts. This identifies TRMT10C-SDR5C1 as a mitochondrial tRNA maturation platform that compensates for structural erosion of mt-tRNAs.","method":"Cryo-EM structures of ELAC2 in complex with TRMT10C, SDR5C1, and divergent mt-tRNA substrates; biochemical processing assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structural evidence combined with functional processing assays showing distinct mechanisms for canonical vs. noncanonical tRNAs","pmids":["39747487"],"is_preprint":false},{"year":2025,"finding":"Kinetic analysis showed that TRMT10C-SDR5C1 encases the entire tRNA substrate; mtRNase P processes pre-tRNAs more efficiently with longer 5' extensions and uses a rigid measuring mechanism for cleavage-site selection. Without interactions with the pre-tRNA, TRMT10C-SDR5C1 cannot stimulate cleavage by PRORP, explaining the complex's inability to process D-armless mitochondrial tRNASer(AGY).","method":"Kinetic analysis with substrate and protein variants, cleavage assays with multiple mitochondrial pre-tRNAs","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — quantitative kinetic analysis with multiple substrate variants, single lab, single study","pmids":["41261864"],"is_preprint":false},{"year":2024,"finding":"N6AMT1 is required for cytosolic translation of TRMT10C (MRPP1) and PRORP (MRPP3); in the absence of N6AMT1, TRMT10C and PRORP protein levels decrease, RNA processing within mitochondria is impaired, leading to accumulation of unprocessed and double-stranded RNA, preventing mitochondrial protein synthesis.","method":"Translational profiling, N6AMT1 knockdown/knockout, Western blotting, mitochondrial RNA processing assays","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic loss-of-function with direct TRMT10C protein level and RNA processing readouts, single lab, single study","pmids":["39503847"],"is_preprint":false},{"year":2013,"finding":"MRPP1 (TRMT10C) co-immunoprecipitates with P32, a mitochondrial protein that also interacts with RNase H1, suggesting MRPP1 participates in a mitochondrial RNA processing complex.","method":"Co-immunoprecipitation","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP experiment identifying an interaction, no functional follow-up specifically for TRMT10C","pmids":["23990920"],"is_preprint":false},{"year":2025,"finding":"A lncRNA-derived micropeptide MRPIP inhibits mtRNase P complex assembly by interacting with HSD17B10 (MRPP2/SDR5C1) at the R25 residue, disrupting HSD17B10 tetramerization and the subsequent HSD17B10-TRMT10C (MRPP1) subcomplex formation, leading to perturbed post-transcriptional RNA processing.","method":"Protein-protein interaction studies, site-directed mutagenesis, biochemical complex assembly assays","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct interaction and mutagenesis showing mechanism of complex disruption, single lab, single study","pmids":["40513568"],"is_preprint":false},{"year":2025,"finding":"In the context of coronary microembolization, reduced succinylation of TRMT10C (at sites recognized by CPT1A) promotes KPNA4-mediated nuclear import via two NLS sequences (KAKR and KKK(X)10KVKK); nuclear TRMT10C then catalyzes m1A modifications on TAFAZZIN and NLRX1 mRNAs, leading to YTHDF2-mediated decay of these transcripts and consequent inflammation, ROS production, and suppression of mitophagy.","method":"Subcellular fractionation, nuclear localization signal mutagenesis, m1A-RIP, TRMT10C knockdown and CPT1A overexpression rescue experiments","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple mechanistic experiments (localization, PTM, mRNA modification, target validation) in single lab, single study","pmids":["40384859"],"is_preprint":false},{"year":2024,"finding":"TRMT10C-mediated m1A methylation of ND5 mRNA is enhanced in an Alzheimer's disease cell model and in AD patients; increased TRMT10C protein levels cause m1A modification of ND5 mRNA leading to translation repression of ND5 and mitochondrial complex I dysfunction.","method":"m1A methylation mapping, TRMT10C overexpression, mitochondrial function assays, patient sample analysis","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional overexpression experiments with direct m1A mapping and translation/functional readouts, single lab, single study","pmids":["38287100"],"is_preprint":false},{"year":2024,"finding":"HSD17B10 K99 succinylation (mediated by CPT1A) maintains mitochondrial RNase P stability; K99R mutation of HSD17B10 impairs its binding to TRMT10C (MRPP1), disrupts RNase P activity, and induces oxidative stress. ASIV treatment restores HSD17B10-TRMT10C interaction and RNase P activity.","method":"Succinylated proteomics, site-directed mutagenesis (K99R), co-immunoprecipitation, RNase P activity assay, molecular docking","journal":"Phytotherapy research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — succinylated proteomics plus mutagenesis plus direct interaction and activity assays, single lab, single study","pmids":["39038923"],"is_preprint":false}],"current_model":"TRMT10C (MRPP1) is a SPOUT-domain methyltransferase that forms the core of two mitochondrial RNA-processing complexes: together with SDR5C1 (MRPP2) it constitutes a tRNA-binding and N1-methylation subcomplex that methylates purines at position 9 of mitochondrial tRNAs using SAM, and together with SDR5C1 and the endonuclease PRORP (MRPP3) it forms the three-subunit mitochondrial RNase P (mtRNase P), which cleaves the 5' leaders of mt-tRNA precursors; cryo-EM structures show TRMT10C-SDR5C1 engages the full tRNA including the anticodon loop and activates PRORP for precise cleavage through an induced-fit mechanism; the TRMT10C-SDR5C1 subcomplex additionally acts as a sequential tRNA maturation platform, retaining tRNA after 5'-processing to enhance downstream 3'-processing by ELAC2 (especially for structurally degenerate mt-tRNAs whose noncanonical processing depends on direct ELAC2-TRMT10C protein-protein contacts) and presenting the nascent tRNA to the CCA-adding enzyme; TRMT10C protein stability depends on SDR5C1, and both subunits are essential for robust PRORP nuclease activation, with disease-causing mutations in any of the three subunits disrupting this coordinated processing and causing mitochondrial dysfunction."},"narrative":{"mechanistic_narrative":"TRMT10C (MRPP1) is a SPOUT-domain methyltransferase that serves as the structural and catalytic core of mitochondrial tRNA maturation, partnering with SDR5C1 (MRPP2) to form a tRNA-binding subcomplex and, upon recruitment of the endonuclease PRORP (MRPP3), the three-subunit mitochondrial RNase P that processes the 5' ends of mt-tRNA precursors and is essential for mitochondrial translation and respiration [PMID:34489609, PMID:21857155]. The TRMT10C C-terminal SPOUT fold binds SAM and catalyzes N1-methylation of purine 9 of mt-tRNAs, while its N-terminus mediates tRNA binding and self-association; the TRMT10C-SDR5C1 N1-methylation subcomplex assembles constitutively, but full RNase P assembles only in the presence of precursor tRNA [PMID:29880640]. Cryo-EM and kinetic analyses establish that TRMT10C-SDR5C1 engages the entire tRNA, including the anticodon loop, and directs and activates PRORP's nuclease domain to the correct cleavage site through an induced-fit measuring mechanism, compensating for the eroded canonical features of structurally degenerate mt-tRNAs [PMID:34489609, PMID:37779095, PMID:41261864]. Beyond 5'-processing, TRMT10C-SDR5C1 functions as a sequential maturation platform: it retains tRNA after RNase P cleavage to enhance ELAC2-catalyzed 3'-processing—especially for noncanonical mt-tRNAs whose maturation depends on direct ELAC2-TRMT10C protein-protein contacts rather than ELAC2-RNA contacts—thereby enforcing the 5'-to-3' processing order, and then presents the nascent tRNA to the CCA-adding enzyme [PMID:29040705, PMID:39516281, PMID:39747487]. TRMT10C protein stability depends on SDR5C1, and disruption of the complex by mutations in TRMT10C or SDR5C1 impairs mt-tRNA processing and mitochondrial protein synthesis [PMID:27132592, PMID:24549042]. Missense variants in TRMT10C cause a mitochondrial disorder, acting by destabilizing MRPP1 protein and impairing mt-RNA processing without affecting methyltransferase activity, a defect rescued by wild-type TRMT10C [PMID:27132592].","teleology":[{"year":2011,"claim":"Established that TRMT10C is functionally required for mitochondrial tRNA 5'-end processing and downstream translation, defining its essential role in mitochondrial gene expression.","evidence":"siRNA knockdown with deep sequencing of transcript ends, Northern blotting, and mitochondrial translation/respiration assays","pmids":["21857155","22028365"],"confidence":"High","gaps":["Did not resolve the molecular architecture of the processing complex","Methyltransferase catalytic contribution not separated from processing role"]},{"year":2014,"claim":"Showed that TRMT10C protein levels depend on its partner SDR5C1, revealing an obligate stability dependence within the methylation subcomplex.","evidence":"HSD10/SDR5C1 siRNA knockdown plus ectopic rescue with Western blotting and precursor tRNA RT-PCR","pmids":["24549042"],"confidence":"Medium","gaps":["Structural basis of the stabilizing interaction not defined","Whether stability loss fully accounts for processing defects unclear"]},{"year":2015,"claim":"Defined the reciprocal TRMT10C-SDR5C1 interaction and showed disease mutations in SDR5C1 disrupt tetramerization and complex formation, linking complex integrity to RNase P activity.","evidence":"Recombinant mutant protein biochemistry, co-immunoprecipitation, methyltransferase and processing assays; plus PRORP crystal structure showing a non-productive active site","pmids":["25925575","25953853"],"confidence":"High","gaps":["Induced-fit activation of PRORP was structural inference, not directly visualized","Order of assembly events not fully resolved"]},{"year":2016,"claim":"Demonstrated TRMT10C is a human disease gene, with missense variants causing mitochondrial dysfunction via protein destabilization independent of methyltransferase activity.","evidence":"Patient fibroblast functional studies, lentiviral wild-type rescue, Northern blotting, mitochondrial protein synthesis assays; Drosophila ortholog Roswell loss-of-function in vivo","pmids":["27132592","27131785"],"confidence":"High","gaps":["Phenotypic spectrum of TRMT10C mutations not fully mapped","Why methylation activity is dispensable for the disease mechanism not resolved"]},{"year":2017,"claim":"Reframed TRMT10C-SDR5C1 from a single-step enzyme to a sequential maturation platform that hands off tRNA between 5'-processing, 3'-processing, and CCA addition.","evidence":"In vitro reconstitution with purified proteins and 22 mitochondrial tRNA substrates, sequential enzyme assays","pmids":["29040705"],"confidence":"High","gaps":["Structural basis for tRNA retention and handoff not yet defined","Why 5 of 22 tRNAs were not enhanced unexplained"]},{"year":2018,"claim":"Mapped TRMT10C domain functions, assigning tRNA binding and self-interaction to the N-terminus and SAM binding/N1-methylation to the C-terminal SPOUT fold, and showed full RNase P assembles only on precursor tRNA.","evidence":"X-ray crystallography, SAXS, interaction and activity assays","pmids":["29880640"],"confidence":"High","gaps":["Conformational changes during PRORP recruitment not captured","Substrate-induced assembly mechanism not visualized at high resolution"]},{"year":2021,"claim":"Provided the high-resolution structural mechanism of substrate recognition, showing how TRMT10C-SDR5C1 binds the full tRNA and recruits/activates PRORP for precise cleavage.","evidence":"Cryo-EM structure of human mtRNase P bound to precursor tRNA with functional validation","pmids":["34489609"],"confidence":"High","gaps":["Dynamics of the induced-fit transition not directly observed","Did not address 3'-processing handoff structurally"]},{"year":2023,"claim":"Quantitatively defined the division of labor, showing PRORP alone binds and cleaves some pre-tRNAs while TRMT10C-SDR5C1 chiefly enforces cleavage-site accuracy and rate, compensating for eroded mt-tRNA features.","evidence":"Kinetic analysis with 12 mitochondrial pre-tRNA substrates and multiple protein combinations","pmids":["37779095","31455609","33380464"],"confidence":"High","gaps":["Determinants of substrate-specific dependence on the subcomplex incompletely defined","How disease-mutant tRNAs evade processing structurally unresolved"]},{"year":2024,"claim":"Extended TRMT10C-SDR5C1 into the 3'-processing complex, with cryo-EM structures of the ELAC2/SDR5C1/TRMT10C assembly explaining the 5'-to-3' processing order and noncanonical tRNA maturation via direct ELAC2-TRMT10C contacts.","evidence":"Cryo-EM of ELAC2/SDR5C1/TRMT10C-tRNA complexes plus biochemical processing assays; kinetic encasement analysis","pmids":["39516281","39747487","41261864"],"confidence":"High","gaps":["How the platform coordinates the temporal transition between RNase P and ELAC2 not fully resolved","Coupling to CCA-adding enzyme not structurally captured"]},{"year":2024,"claim":"Identified upstream and regulatory inputs controlling TRMT10C abundance and complex assembly, including N6AMT1-dependent cytosolic translation and post-translational/micropeptide control of the subcomplex.","evidence":"N6AMT1 knockdown/translational profiling; MRPIP micropeptide interaction and mutagenesis; HSD17B10 succinylation proteomics and mutagenesis","pmids":["39503847","40513568","39038923"],"confidence":"Medium","gaps":["Physiological conditions regulating these inputs unclear","Whether these regulatory layers operate in normal tissue not established"]},{"year":2025,"claim":"Reported context-dependent noncanonical roles for TRMT10C, including succinylation-controlled nuclear import driving m1A modification of nuclear-encoded mRNAs and elevated mitochondrial ND5 mRNA m1A in disease models.","evidence":"Subcellular fractionation, NLS mutagenesis, m1A-RIP, knockdown/overexpression rescue in coronary microembolization and Alzheimer's disease models","pmids":["40384859","38287100"],"confidence":"Medium","gaps":["Nuclear/mRNA-modifying activity not independently confirmed beyond single disease-model studies","Relationship between canonical mitochondrial role and these moonlighting functions unresolved"]},{"year":null,"claim":"How TRMT10C-SDR5C1 temporally coordinates the complete relay from 5'-processing through 3'-processing and CCA addition, and whether its reported nuclear mRNA-modifying functions occur under physiological conditions, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model spanning all sequential maturation steps","Nuclear localization and mRNA m1A roles rest on single-lab disease-model studies"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,3,9,11]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,2,9]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5,10]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[6,12]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,6]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,18]}],"complexes":["mitochondrial RNase P (TRMT10C-SDR5C1-PRORP)","TRMT10C-SDR5C1 N1-methylation subcomplex","mitochondrial RNase Z complex (ELAC2-SDR5C1-TRMT10C)"],"partners":["SDR5C1","PRORP","ELAC2","N6AMT1","KPNA4","P32"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7L0Y3","full_name":"tRNA methyltransferase 10 homolog C","aliases":["HBV pre-S2 trans-regulated protein 2","Mitochondrial ribonuclease P protein 1","Mitochondrial RNase P protein 1","RNA (guanine-9-)-methyltransferase domain-containing protein 1","Renal carcinoma antigen NY-REN-49","mRNA methyladenosine-N(1)-methyltransferase","tRNA (adenine(9)-N(1))-methyltransferase","tRNA (guanine(9)-N(1))-methyltransferase"],"length_aa":403,"mass_kda":47.3,"function":"Mitochondrial tRNA N(1)-methyltransferase involved in mitochondrial tRNA maturation (PubMed:18984158, PubMed:21593607, PubMed:23042678, PubMed:27132592). Component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3, which cleaves tRNA molecules in their 5'-ends (PubMed:18984158). Together with HSD17B10/MRPP2, forms a subcomplex of the mitochondrial ribonuclease P, named MRPP1-MRPP2 subcomplex, which displays functions that are independent of the ribonuclease P activity (PubMed:23042678, PubMed:29040705). The MRPP1-MRPP2 subcomplex catalyzes the formation of N(1)-methylguanine and N(1)-methyladenine at position 9 (m1G9 and m1A9, respectively) in tRNAs; TRMT10C/MRPP1 acting as the catalytic N(1)-methyltransferase subunit (PubMed:23042678). The MRPP1-MRPP2 subcomplex also acts as a tRNA maturation platform: following 5'-end cleavage by the mitochondrial ribonuclease P complex, the MRPP1-MRPP2 subcomplex enhances the efficiency of 3'-processing catalyzed by ELAC2, retains the tRNA product after ELAC2 processing and presents the nascent tRNA to the mitochondrial CCA tRNA nucleotidyltransferase TRNT1 enzyme (PubMed:29040705). In addition to tRNA N(1)-methyltransferase activity, TRMT10C/MRPP1 also acts as a mRNA N(1)-methyltransferase by mediating methylation of adenosine residues at the N(1) position of MT-ND5 mRNA (PubMed:29072297). Associates with mitochondrial DNA complexes at the nucleoids to initiate RNA processing and ribosome assembly","subcellular_location":"Mitochondrion matrix, mitochondrion nucleoid","url":"https://www.uniprot.org/uniprotkb/Q7L0Y3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRMT10C","classification":"Not Classified","n_dependent_lines":500,"n_total_lines":1208,"dependency_fraction":0.4139072847682119},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SSB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TRMT10C","total_profiled":1310},"omim":[{"mim_id":"616974","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 30; COXPD30","url":"https://www.omim.org/entry/616974"},{"mim_id":"615423","title":"tRNA METHYLTRANSFERASE 10C, MITOCHONDRIAL RNAse P SUBUNIT; TRMT10C","url":"https://www.omim.org/entry/615423"},{"mim_id":"609060","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 1; COXPD1","url":"https://www.omim.org/entry/609060"},{"mim_id":"605367","title":"ELAC RIBONUCLEASE Z 2; ELAC2","url":"https://www.omim.org/entry/605367"},{"mim_id":"516005","title":"COMPLEX I, SUBUNIT ND5; MTND5","url":"https://www.omim.org/entry/516005"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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The entire TRMT10C interacts with MRPP2 (SDR5C1) to form the N1-methylation subcomplex, whereas the full MRPP1-MRPP2-MRPP3 RNase P complex assembles only in the presence of precursor tRNA.\",\n      \"method\": \"X-ray crystallography, SAXS, interaction assays, activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus SAXS plus functional assays in one study, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"29880640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRMT10C (MRPP1) and SDR5C1 (MRPP2) form a tRNA-maturation platform: the MRPP1/2 subcomplex retains the tRNA product after 5'-processing by RNase P, significantly enhances efficiency of ELAC2-catalyzed 3'-processing for 17 of 22 mitochondrial tRNAs, and then presents the nascent tRNA to the mitochondrial CCA-adding enzyme.\",\n      \"method\": \"In vitro reconstitution assays with purified proteins and mitochondrial tRNA substrates\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with multiple tRNA substrates and sequential enzyme assays, single lab but multiple orthogonal functional experiments\",\n      \"pmids\": [\"29040705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Patients with TRMT10C missense variants (p.Arg181Leu and p.Thr272Ala) showed decreased MRPP1 protein levels and increased mt-RNA precursors indicative of impaired mt-RNA processing and defective mitochondrial protein synthesis; lentiviral transduction of wild-type TRMT10C rescued mt-RNA processing and mitochondrial protein synthesis defects. The variants affect MRPP1 protein stability and mt-tRNA processing without affecting m1R9 methyltransferase activity.\",\n      \"method\": \"Patient fibroblast functional studies, lentiviral rescue, Northern blotting, mitochondrial protein synthesis assay\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue experiment with wild-type TRMT10C plus multiple biochemical readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27132592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRMT10C interacts with SDR5C1 (MRPP2/HSD10); pathogenic SDR5C1 mutations disrupt homotetramerization of SDR5C1 and/or impair its interaction with TRMT10C, leading to impaired tRNA processing and methylation activities of the mtRNase P complex.\",\n      \"method\": \"Biochemical characterization of recombinant mutant proteins, co-immunoprecipitation, enzymatic activity assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction studies plus functional methyltransferase and processing assays with disease mutants, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25925575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of the MRPP3 (PRORP) nuclease subunit showed a distorted, non-productive active site, leading to the proposed mechanism that PRORP switches to a productive state only upon association with MRPP1 (TRMT10C) and MRPP2 through an induced-fit process when pre-tRNA substrate is present.\",\n      \"method\": \"X-ray crystallography of MRPP3, structural analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure of a subunit with mechanistic interpretation, but mechanistic conclusion about TRMT10C-mediated activation is structural inference from a single lab\",\n      \"pmids\": [\"25953853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MRPP1 (TRMT10C) is essential for mt-tRNA processing (5' end), RNA modification, translation, and mitochondrial respiration; MRPP1 and MRPP3 together process the 5' ends of tRNAs and the 5' non-tRNA-containing site of the CO1 transcript.\",\n      \"method\": \"Deep sequencing of transcript ends after siRNA knockdown, Northern blotting, mitochondrial translation assay\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockdown with multiple orthogonal readouts (sequencing, Northern blot, translation, respiration), replicated across multiple studies\",\n      \"pmids\": [\"21857155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MRPP1 (TRMT10C) is required for the processing of mitochondrial long noncoding RNAs generated from the mitochondrial genome.\",\n      \"method\": \"Deep sequencing, Northern blotting, strand-specific qRT-PCR with MRPP1 knockdown\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — knockdown with multiple readouts (sequencing, Northern blot) but single lab, single study\",\n      \"pmids\": [\"22028365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HSD10 (SDR5C1/MRPP2) is required for maintaining normal MRPP1 (TRMT10C) protein levels; knockdown of HSD10 causes reduction in MRPP1 protein (but not MRPP3) and impairs processing of precursor tRNAs from the mitochondrial heavy strand. Ectopic expression of HSD10 restores MRPP1 levels and partially rescues RNA processing.\",\n      \"method\": \"siRNA knockdown, ectopic overexpression, Western blotting, patient fibroblast studies, RT-PCR of precursor tRNAs\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown plus rescue experiments with multiple readouts, single lab; reveals TRMT10C stability dependence on SDR5C1\",\n      \"pmids\": [\"24549042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Purified mtRNase P (TRMT10C/MRPP1, MRPP2, MRPP3) recognizes, cleaves, and methylates a subset but not all mitochondrial pre-tRNAs in vitro; addition of SAM (the TRMT10C cofactor) enhances binding and cleavage of some mitochondrial pre-tRNAs, and the presence of MRPP3 can enhance the methylation activity of the MRPP1/2 subcomplex.\",\n      \"method\": \"In vitro cleavage and methylation assays with purified recombinant mtRNase P components\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with purified proteins, single lab, single study\",\n      \"pmids\": [\"31455609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Kinetic analysis showed that PRORP (MRPP3) alone can bind pre-tRNAs with nanomolar affinity and cleave some at reduced efficiency without TRMT10C-SDR5C1. The main function of the TRMT10C-SDR5C1 subcomplex is to direct PRORP's nuclease domain to the correct cleavage site, increasing the rate and accuracy of cleavage, likely by compensating for structural erosion of canonical features in mitochondrial tRNAs.\",\n      \"method\": \"Kinetic analysis with purified recombinant proteins, 12 different mitochondrial pre-tRNA substrates\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative kinetics with 12 substrates, multiple protein combinations, single lab with rigorous controls\",\n      \"pmids\": [\"37779095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Disease-linked mutations in mitochondrial pre-tRNAIle, pre-tRNALeu(UUR), and pre-tRNAMet reduce MRPP1 (TRMT10C)-catalyzed methylation activity (up to ~90% reduction) and 5' end processing by mtRNase P; several mutations weaken pre-tRNA binding affinity (2- to 6-fold higher Ks than wild-type).\",\n      \"method\": \"In vitro methylation and cleavage assays with recombinant mtRNase P and disease-mutant pre-tRNA substrates, binding assays\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with quantitative kinetics, single lab, single study\",\n      \"pmids\": [\"33380464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Drosophila, the MRPP1 ortholog Roswell is essential for development, localizes to mitochondria, and its loss causes defective mitochondrial tRNA processing and mitochondrial dysfunction in vivo.\",\n      \"method\": \"Homology-based identification, genetic knockdown/overexpression, immunofluorescence localization, mitochondrial tRNA processing assays, lethality assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic loss-of-function with direct tRNA processing readout in Drosophila model, corroborated by human disease data\",\n      \"pmids\": [\"27131785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Novel HSD17B10 missense mutations (p.V12L and p.V176M) reduce dehydrogenase, methyltransferase, and tRNA processing activities of the MRPP2-TRMT10C complex; p.V12L reduces SDR5C1 stability, while p.V176M impairs kinetics and complex formation with TRMT10C.\",\n      \"method\": \"Biochemical characterization of recombinant mutant proteins, enzymatic activity assays, complex formation assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical assays with recombinant proteins, single lab, single study\",\n      \"pmids\": [\"28888424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A novel HSD17B10 p.K212E mutation impairs SDR5C1-dependent mitochondrial RNase P activities (5'-processing and methylation of purine-9 of mitochondrial tRNAs), suggesting pathogenicity through general mitochondrial dysfunction caused by reduced maturation of mitochondrial tRNAs.\",\n      \"method\": \"Functional assays of mitochondrial RNase P activity in patient cells and in vitro with recombinant mutant protein\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional assays with patient mutation and recombinant protein, single lab, single study\",\n      \"pmids\": [\"26950678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of the mitochondrial RNase Z complex (ELAC2/SDR5C1/TRMT10C) bound to mitochondrial tRNAHis revealed that TRMT10C-SDR5C1 participates in the 3'-processing complex and provides the molecular rationale for the 5'-to-3' tRNA processing order in mitochondria.\",\n      \"method\": \"Cryo-EM structure determination of the ELAC2/SDR5C1/TRMT10C complex with tRNA substrate\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structures at multiple maturation states, single lab with high-resolution structural evidence\",\n      \"pmids\": [\"39516281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRMT10C and SDR5C1 specifically facilitate ELAC2-mediated 3'-end processing of structurally degenerate mitochondrial tRNAs lacking the canonical elbow; processing of noncanonical mt-tRNAs depends on direct protein-protein interactions between ELAC2 and TRMT10C rather than direct ELAC2-RNA contacts. This identifies TRMT10C-SDR5C1 as a mitochondrial tRNA maturation platform that compensates for structural erosion of mt-tRNAs.\",\n      \"method\": \"Cryo-EM structures of ELAC2 in complex with TRMT10C, SDR5C1, and divergent mt-tRNA substrates; biochemical processing assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structural evidence combined with functional processing assays showing distinct mechanisms for canonical vs. noncanonical tRNAs\",\n      \"pmids\": [\"39747487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Kinetic analysis showed that TRMT10C-SDR5C1 encases the entire tRNA substrate; mtRNase P processes pre-tRNAs more efficiently with longer 5' extensions and uses a rigid measuring mechanism for cleavage-site selection. Without interactions with the pre-tRNA, TRMT10C-SDR5C1 cannot stimulate cleavage by PRORP, explaining the complex's inability to process D-armless mitochondrial tRNASer(AGY).\",\n      \"method\": \"Kinetic analysis with substrate and protein variants, cleavage assays with multiple mitochondrial pre-tRNAs\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — quantitative kinetic analysis with multiple substrate variants, single lab, single study\",\n      \"pmids\": [\"41261864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"N6AMT1 is required for cytosolic translation of TRMT10C (MRPP1) and PRORP (MRPP3); in the absence of N6AMT1, TRMT10C and PRORP protein levels decrease, RNA processing within mitochondria is impaired, leading to accumulation of unprocessed and double-stranded RNA, preventing mitochondrial protein synthesis.\",\n      \"method\": \"Translational profiling, N6AMT1 knockdown/knockout, Western blotting, mitochondrial RNA processing assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic loss-of-function with direct TRMT10C protein level and RNA processing readouts, single lab, single study\",\n      \"pmids\": [\"39503847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MRPP1 (TRMT10C) co-immunoprecipitates with P32, a mitochondrial protein that also interacts with RNase H1, suggesting MRPP1 participates in a mitochondrial RNA processing complex.\",\n      \"method\": \"Co-immunoprecipitation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP experiment identifying an interaction, no functional follow-up specifically for TRMT10C\",\n      \"pmids\": [\"23990920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A lncRNA-derived micropeptide MRPIP inhibits mtRNase P complex assembly by interacting with HSD17B10 (MRPP2/SDR5C1) at the R25 residue, disrupting HSD17B10 tetramerization and the subsequent HSD17B10-TRMT10C (MRPP1) subcomplex formation, leading to perturbed post-transcriptional RNA processing.\",\n      \"method\": \"Protein-protein interaction studies, site-directed mutagenesis, biochemical complex assembly assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct interaction and mutagenesis showing mechanism of complex disruption, single lab, single study\",\n      \"pmids\": [\"40513568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In the context of coronary microembolization, reduced succinylation of TRMT10C (at sites recognized by CPT1A) promotes KPNA4-mediated nuclear import via two NLS sequences (KAKR and KKK(X)10KVKK); nuclear TRMT10C then catalyzes m1A modifications on TAFAZZIN and NLRX1 mRNAs, leading to YTHDF2-mediated decay of these transcripts and consequent inflammation, ROS production, and suppression of mitophagy.\",\n      \"method\": \"Subcellular fractionation, nuclear localization signal mutagenesis, m1A-RIP, TRMT10C knockdown and CPT1A overexpression rescue experiments\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple mechanistic experiments (localization, PTM, mRNA modification, target validation) in single lab, single study\",\n      \"pmids\": [\"40384859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRMT10C-mediated m1A methylation of ND5 mRNA is enhanced in an Alzheimer's disease cell model and in AD patients; increased TRMT10C protein levels cause m1A modification of ND5 mRNA leading to translation repression of ND5 and mitochondrial complex I dysfunction.\",\n      \"method\": \"m1A methylation mapping, TRMT10C overexpression, mitochondrial function assays, patient sample analysis\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional overexpression experiments with direct m1A mapping and translation/functional readouts, single lab, single study\",\n      \"pmids\": [\"38287100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HSD17B10 K99 succinylation (mediated by CPT1A) maintains mitochondrial RNase P stability; K99R mutation of HSD17B10 impairs its binding to TRMT10C (MRPP1), disrupts RNase P activity, and induces oxidative stress. ASIV treatment restores HSD17B10-TRMT10C interaction and RNase P activity.\",\n      \"method\": \"Succinylated proteomics, site-directed mutagenesis (K99R), co-immunoprecipitation, RNase P activity assay, molecular docking\",\n      \"journal\": \"Phytotherapy research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — succinylated proteomics plus mutagenesis plus direct interaction and activity assays, single lab, single study\",\n      \"pmids\": [\"39038923\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRMT10C (MRPP1) is a SPOUT-domain methyltransferase that forms the core of two mitochondrial RNA-processing complexes: together with SDR5C1 (MRPP2) it constitutes a tRNA-binding and N1-methylation subcomplex that methylates purines at position 9 of mitochondrial tRNAs using SAM, and together with SDR5C1 and the endonuclease PRORP (MRPP3) it forms the three-subunit mitochondrial RNase P (mtRNase P), which cleaves the 5' leaders of mt-tRNA precursors; cryo-EM structures show TRMT10C-SDR5C1 engages the full tRNA including the anticodon loop and activates PRORP for precise cleavage through an induced-fit mechanism; the TRMT10C-SDR5C1 subcomplex additionally acts as a sequential tRNA maturation platform, retaining tRNA after 5'-processing to enhance downstream 3'-processing by ELAC2 (especially for structurally degenerate mt-tRNAs whose noncanonical processing depends on direct ELAC2-TRMT10C protein-protein contacts) and presenting the nascent tRNA to the CCA-adding enzyme; TRMT10C protein stability depends on SDR5C1, and both subunits are essential for robust PRORP nuclease activation, with disease-causing mutations in any of the three subunits disrupting this coordinated processing and causing mitochondrial dysfunction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRMT10C (MRPP1) is a SPOUT-domain methyltransferase that serves as the structural and catalytic core of mitochondrial tRNA maturation, partnering with SDR5C1 (MRPP2) to form a tRNA-binding subcomplex and, upon recruitment of the endonuclease PRORP (MRPP3), the three-subunit mitochondrial RNase P that processes the 5' ends of mt-tRNA precursors and is essential for mitochondrial translation and respiration [#0, #6]. The TRMT10C C-terminal SPOUT fold binds SAM and catalyzes N1-methylation of purine 9 of mt-tRNAs, while its N-terminus mediates tRNA binding and self-association; the TRMT10C-SDR5C1 N1-methylation subcomplex assembles constitutively, but full RNase P assembles only in the presence of precursor tRNA [#1]. Cryo-EM and kinetic analyses establish that TRMT10C-SDR5C1 engages the entire tRNA, including the anticodon loop, and directs and activates PRORP's nuclease domain to the correct cleavage site through an induced-fit measuring mechanism, compensating for the eroded canonical features of structurally degenerate mt-tRNAs [#0, #10, #17]. Beyond 5'-processing, TRMT10C-SDR5C1 functions as a sequential maturation platform: it retains tRNA after RNase P cleavage to enhance ELAC2-catalyzed 3'-processing—especially for noncanonical mt-tRNAs whose maturation depends on direct ELAC2-TRMT10C protein-protein contacts rather than ELAC2-RNA contacts—thereby enforcing the 5'-to-3' processing order, and then presents the nascent tRNA to the CCA-adding enzyme [#2, #15, #16]. TRMT10C protein stability depends on SDR5C1, and disruption of the complex by mutations in TRMT10C or SDR5C1 impairs mt-tRNA processing and mitochondrial protein synthesis [#3, #8]. Missense variants in TRMT10C cause a mitochondrial disorder, acting by destabilizing MRPP1 protein and impairing mt-RNA processing without affecting methyltransferase activity, a defect rescued by wild-type TRMT10C [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that TRMT10C is functionally required for mitochondrial tRNA 5'-end processing and downstream translation, defining its essential role in mitochondrial gene expression.\",\n      \"evidence\": \"siRNA knockdown with deep sequencing of transcript ends, Northern blotting, and mitochondrial translation/respiration assays\",\n      \"pmids\": [\"21857155\", \"22028365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular architecture of the processing complex\", \"Methyltransferase catalytic contribution not separated from processing role\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed that TRMT10C protein levels depend on its partner SDR5C1, revealing an obligate stability dependence within the methylation subcomplex.\",\n      \"evidence\": \"HSD10/SDR5C1 siRNA knockdown plus ectopic rescue with Western blotting and precursor tRNA RT-PCR\",\n      \"pmids\": [\"24549042\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the stabilizing interaction not defined\", \"Whether stability loss fully accounts for processing defects unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the reciprocal TRMT10C-SDR5C1 interaction and showed disease mutations in SDR5C1 disrupt tetramerization and complex formation, linking complex integrity to RNase P activity.\",\n      \"evidence\": \"Recombinant mutant protein biochemistry, co-immunoprecipitation, methyltransferase and processing assays; plus PRORP crystal structure showing a non-productive active site\",\n      \"pmids\": [\"25925575\", \"25953853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Induced-fit activation of PRORP was structural inference, not directly visualized\", \"Order of assembly events not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated TRMT10C is a human disease gene, with missense variants causing mitochondrial dysfunction via protein destabilization independent of methyltransferase activity.\",\n      \"evidence\": \"Patient fibroblast functional studies, lentiviral wild-type rescue, Northern blotting, mitochondrial protein synthesis assays; Drosophila ortholog Roswell loss-of-function in vivo\",\n      \"pmids\": [\"27132592\", \"27131785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phenotypic spectrum of TRMT10C mutations not fully mapped\", \"Why methylation activity is dispensable for the disease mechanism not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Reframed TRMT10C-SDR5C1 from a single-step enzyme to a sequential maturation platform that hands off tRNA between 5'-processing, 3'-processing, and CCA addition.\",\n      \"evidence\": \"In vitro reconstitution with purified proteins and 22 mitochondrial tRNA substrates, sequential enzyme assays\",\n      \"pmids\": [\"29040705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for tRNA retention and handoff not yet defined\", \"Why 5 of 22 tRNAs were not enhanced unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped TRMT10C domain functions, assigning tRNA binding and self-interaction to the N-terminus and SAM binding/N1-methylation to the C-terminal SPOUT fold, and showed full RNase P assembles only on precursor tRNA.\",\n      \"evidence\": \"X-ray crystallography, SAXS, interaction and activity assays\",\n      \"pmids\": [\"29880640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational changes during PRORP recruitment not captured\", \"Substrate-induced assembly mechanism not visualized at high resolution\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the high-resolution structural mechanism of substrate recognition, showing how TRMT10C-SDR5C1 binds the full tRNA and recruits/activates PRORP for precise cleavage.\",\n      \"evidence\": \"Cryo-EM structure of human mtRNase P bound to precursor tRNA with functional validation\",\n      \"pmids\": [\"34489609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of the induced-fit transition not directly observed\", \"Did not address 3'-processing handoff structurally\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Quantitatively defined the division of labor, showing PRORP alone binds and cleaves some pre-tRNAs while TRMT10C-SDR5C1 chiefly enforces cleavage-site accuracy and rate, compensating for eroded mt-tRNA features.\",\n      \"evidence\": \"Kinetic analysis with 12 mitochondrial pre-tRNA substrates and multiple protein combinations\",\n      \"pmids\": [\"37779095\", \"31455609\", \"33380464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of substrate-specific dependence on the subcomplex incompletely defined\", \"How disease-mutant tRNAs evade processing structurally unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended TRMT10C-SDR5C1 into the 3'-processing complex, with cryo-EM structures of the ELAC2/SDR5C1/TRMT10C assembly explaining the 5'-to-3' processing order and noncanonical tRNA maturation via direct ELAC2-TRMT10C contacts.\",\n      \"evidence\": \"Cryo-EM of ELAC2/SDR5C1/TRMT10C-tRNA complexes plus biochemical processing assays; kinetic encasement analysis\",\n      \"pmids\": [\"39516281\", \"39747487\", \"41261864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the platform coordinates the temporal transition between RNase P and ELAC2 not fully resolved\", \"Coupling to CCA-adding enzyme not structurally captured\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified upstream and regulatory inputs controlling TRMT10C abundance and complex assembly, including N6AMT1-dependent cytosolic translation and post-translational/micropeptide control of the subcomplex.\",\n      \"evidence\": \"N6AMT1 knockdown/translational profiling; MRPIP micropeptide interaction and mutagenesis; HSD17B10 succinylation proteomics and mutagenesis\",\n      \"pmids\": [\"39503847\", \"40513568\", \"39038923\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological conditions regulating these inputs unclear\", \"Whether these regulatory layers operate in normal tissue not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reported context-dependent noncanonical roles for TRMT10C, including succinylation-controlled nuclear import driving m1A modification of nuclear-encoded mRNAs and elevated mitochondrial ND5 mRNA m1A in disease models.\",\n      \"evidence\": \"Subcellular fractionation, NLS mutagenesis, m1A-RIP, knockdown/overexpression rescue in coronary microembolization and Alzheimer's disease models\",\n      \"pmids\": [\"40384859\", \"38287100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear/mRNA-modifying activity not independently confirmed beyond single disease-model studies\", \"Relationship between canonical mitochondrial role and these moonlighting functions unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRMT10C-SDR5C1 temporally coordinates the complete relay from 5'-processing through 3'-processing and CCA addition, and whether its reported nuclear mRNA-modifying functions occur under physiological conditions, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model spanning all sequential maturation steps\", \"Nuclear localization and mRNA m1A roles rest on single-lab disease-model studies\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 3, 9, 11]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 2, 9]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [6, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 18]}\n    ],\n    \"complexes\": [\n      \"mitochondrial RNase P (TRMT10C-SDR5C1-PRORP)\",\n      \"TRMT10C-SDR5C1 N1-methylation subcomplex\",\n      \"mitochondrial RNase Z complex (ELAC2-SDR5C1-TRMT10C)\"\n    ],\n    \"partners\": [\n      \"SDR5C1\",\n      \"PRORP\",\n      \"ELAC2\",\n      \"N6AMT1\",\n      \"KPNA4\",\n      \"P32\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}