{"gene":"TOMM7","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1996,"finding":"Tom7 is an integral membrane subunit of the mitochondrial outer membrane TOM translocase. Deletion of TOM7 inhibits import of the outer membrane protein porin and strongly impairs two-step preprotein import into the mitochondrial interior. Loss of Tom7 stabilizes interactions between receptors Tom20 and Tom22 and the import pore Tom40, indicating Tom7 exerts a destabilizing effect on part of the outer membrane translocase, while Tom6 stabilizes these interactions. Genetic synthetic growth defects of tom7Δ tom20Δ and tom7Δ tom6Δ double mutants confirmed functional relationships between Tom7, Tom20, and Tom6.","method":"Yeast genetics (deletion mutants, double mutants), blue native PAGE, import assays in vitro, biochemical fractionation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic epistasis, biochemical fractionation, import assays), foundational study replicated by subsequent work","pmids":["8641278"],"is_preprint":false},{"year":2001,"finding":"Tom6 and Tom7 are subunits of the Neurospora crassa TOM core complex. Cross-linking experiments showed both proteins are in direct contact with Tom40. Precursors of Tom6 and Tom7 insert into the outer membrane in vitro and assemble into authentic TOM complexes; assembly shares a common binding site with the general import pathway and requires the integrity of TOM receptor components.","method":"Cross-linking in vivo, in vitro import/assembly assays, blue native PAGE, hybrid protein analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct cross-linking demonstrating physical contact, in vitro reconstitution of assembly, multiple orthogonal methods","pmids":["11278536"],"is_preprint":false},{"year":2002,"finding":"Tom7 is a tail-anchored protein; the carboxy-terminal 33 amino acids contain the targeting information for the mitochondrial outer membrane. A conserved proline residue within the transmembrane segment is required for efficient targeting of Tom7 to the outer membrane. An equivalent proline residue is important for targeting each of the other three tail-anchored proteins (Tom5, Tom6, Tom22) that associate with Tom40 to form the TOM core.","method":"Deletion/truncation analysis, mutagenesis of conserved proline, fluorescence microscopy, import assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus import assays, single lab, two complementary methods","pmids":["11943179"],"is_preprint":false},{"year":2002,"finding":"Human TOMM7 is imported into mitochondria in a nucleotide-independent manner and is anchored to the outer membrane with its C terminus facing the intermembrane space. Human Tom7 assembles first into an ~120 kDa import intermediate containing Tom40 but lacking receptor components, which is then chased to the stable ~380 kDa TOM complex additionally containing Tom22. Tom22 is rate-limiting for TOM complex formation, as Tom22 overexpression accelerates Tom7 assembly into the 380 kDa complex.","method":"Import assays in HeLa cell mitochondria, blue native PAGE, supershift analysis with TOM-specific antibodies, Tom22 overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical methods (import, BN-PAGE, antibody supershift), characterization of human protein assembly pathway","pmids":["12198123"],"is_preprint":false},{"year":2006,"finding":"Tom7 functions in an antagonistic manner to Mdm10 in beta-barrel protein biogenesis. Tom7 promotes segregation of Mdm10 from the SAM(holo) complex into a low molecular mass form. Upon deletion of Tom7, the fraction of Mdm10 in the SAM(holo) complex is significantly increased, selectively promoting Tom40 assembly but not porin assembly.","method":"Yeast genetics (TOM7 deletion), blue native PAGE, in vitro import/assembly assays, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic deletion combined with biochemical reconstitution and BN-PAGE, replicated by subsequent studies from other labs","pmids":["16760475"],"is_preprint":false},{"year":2010,"finding":"Tom7 directly interacts with Tom40 through its transmembrane segment and with Mdm10, as shown by site-specific photocross-linking in vivo. Tom7 recruits Mdm10 and enhances its association with the MMM1 complex, thereby regulating the timing of Tom40 release from the TOB/SAM complex for subsequent assembly into the TOM40 complex. Depletion of Tom7 decreased transient accumulation of Tom40 at the TOB complex, while overexpression of Tom7 enhanced it.","method":"Site-specific photocross-linking in vivo, in vitro import assays, BN-PAGE, Tom7 depletion and overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site-specific photocross-linking identifying direct contacts, combined with functional gain/loss-of-function assays","pmids":["21036907"],"is_preprint":false},{"year":2010,"finding":"Tom7 plays an inhibitory role at two distinct steps in TOM complex biogenesis: (1) Tom7 acts antagonistically to Tom5 and Tom6 at an early stage of Tom40 assembly at the SAM complex; (2) Tom7 interacts with free Mdm10 (not bound to the SAM complex), thereby promoting dissociation of the SAM-Mdm10 complex and delaying Tom22 assembly with Tom40 at a late stage. Thus Tom7 modulates biogenesis of both the beta-barrel protein Tom40 and the alpha-helical Tom22.","method":"Yeast genetics, blue native PAGE, in vitro import assays, co-immunoprecipitation","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, complementary to parallel study (PMID 21036907), identifies two mechanistically distinct inhibitory steps","pmids":["21059357"],"is_preprint":false},{"year":2018,"finding":"Tomm7 deficit in endothelial cells induces increased import of Rac1 protein into mitochondria and facilitates mitochondrial Rac1-coupled redox signaling, causing angiogenic impairment that underlies cerebrovascular network malformation. Endothelial-specific transgenesis of tomm7 restored cerebrovascular anomalies in Tomm7-knockout mice.","method":"Loss-of-function genetic screening in zebrafish, conditional knockout mice, endothelial-specific transgenesis, vascular imaging, mitochondrial protein import assays","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiment in two model organisms with mechanistic follow-up on Rac1 import, single lab","pmids":["30354240"],"is_preprint":false},{"year":2019,"finding":"Tom7 is required for PINK1 accumulation at the outer mitochondrial membrane upon mitochondrial depolarization. Deletion of Tom7 allows PINK1 to be imported into depolarized mitochondria where it is cleaved by the OMA1 protease rather than arrested at the outer membrane. PINK1 contains a negatively charged amino acid cluster motif C-terminal to its transmembrane domain that is required for import arrest; mutagenesis of this motif phenocopies Tom7 deletion. Thus, ΔΨm-loss-dependent PINK1 import arrest involves an actively regulated 'tug of war' between Tom7 (promoting outer membrane retention) and OMA1 (promoting PINK1 cleavage after inner-membrane import).","method":"Tom7 knockout cell lines, PINK1 mutagenesis, OMA1 suppression, import assays, protease protection assays, cell biology","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic deletion, site-directed mutagenesis, protease cleavage assays, epistasis with OMA1, multiple orthogonal methods in one study","pmids":["30733118"],"is_preprint":false},{"year":2022,"finding":"A homozygous missense variant in TOMM7 (p.Pro29Leu) causes an autosomal recessive progeroid syndrome in a human patient. Proteomic comparison of mitochondria from patient-derived fibroblasts vs. controls revealed increased abundance of oxidative phosphorylation proteins and reduced abundance of phospholipid metabolism proteins, along with elevated basal and maximal oxygen consumption rates, consistent with altered mitochondrial protein import due to biallelic loss-of-function TOMM7.","method":"Exome sequencing, mitochondrial proteomics (quantitative MS), oxygen consumption rate measurement in patient-derived fibroblasts","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic and bioenergetic profiling of patient cells, single family, no reconstitution or rescue experiment","pmids":["36282599"],"is_preprint":false},{"year":2022,"finding":"A homozygous hypomorphic variant in TOMM7 (p.Trp25Arg) causes syndromic short stature with mitochondrial dysfunction. Mouse models homozygous for this variant show a milder phenotype than complete Tomm7 deletion mice. Tomm7 deficiency causes an uncoupling between oxidation and ATP synthesis without impairing the ETC or tricarboxylic acid cycle function, as evidenced by increased oxygen consumption with normal responses to ETC inhibitors.","method":"Mouse knock-in and knockout models, oxygen consumption assays, ETC inhibitor assays, patient variant analysis","journal":"HGG advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comparative mouse models (hypomorph vs. full KO), functional bioenergetics, single lab","pmids":["36299998"],"is_preprint":false},{"year":2025,"finding":"TOMM7 regulates PINK1/Parkin-mediated mitophagy in kidney tubular cells by modulating the intracellular redistribution of phospholipase PLA2G6 between the nucleus and mitochondria. Tomm7 overexpression in db/db mice restored PINK1/Parkin-mediated mitophagy and alleviated kidney injury. ZBTB12 was identified as a transcriptional repressor of TOMM7.","method":"Tomm7 overexpression in db/db mice, HK-2 cell overexpression/knockdown, mitophagy flux assays, subcellular fractionation of PLA2G6, ChIP/transcription factor binding assays","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo rescue with mechanistic follow-up on PLA2G6 redistribution, single lab","pmids":["41276015"],"is_preprint":false},{"year":2025,"finding":"CRISPR-Cas9 knockout of TOM7 in iPSC-derived dopaminergic neurons decreased ubiquitin pSer65 upregulation during mitophagy activation (induced by exogenous stimuli), confirming TOM7's role in the PINK1-PARKIN mitophagy pathway in a human neuronal model.","method":"High-throughput arrayed CRISPR-Cas9 KO screen in iPSC-derived dopaminergic neurons, high-content immunofluorescence imaging, machine learning analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with quantitative phenotypic readout in disease-relevant human cell model, preprint, single lab","pmids":["bio_10.1101_2025.06.10.658840"],"is_preprint":true}],"current_model":"TOMM7 encodes a small tail-anchored integral membrane subunit of the TOM translocase of the outer mitochondrial membrane that plays a dynamic regulatory role: it destabilizes TOM receptor–pore interactions to modulate preprotein translocation, directly contacts Tom40 via its transmembrane segment, sequesters Mdm10 away from the SAM/TOB complex to differentially regulate beta-barrel protein assembly (promoting porin but inhibiting Tom40 maturation timing), and is specifically required for arrest of PINK1 at the outer membrane upon mitochondrial depolarization by opposing OMA1-mediated PINK1 cleavage—thereby controlling PINK1/Parkin-dependent mitophagy; loss-of-function variants cause a human progeroid syndrome with mitochondrial import defects."},"narrative":{"mechanistic_narrative":"TOMM7 encodes a small tail-anchored integral membrane subunit of the TOM translocase of the mitochondrial outer membrane that exerts a dynamic, predominantly destabilizing regulatory influence on preprotein import [PMID:8641278]. Anchored in the outer membrane via a C-terminal transmembrane segment whose conserved proline is required for targeting, Tom7 makes direct contact with the import pore Tom40 [PMID:11278536, PMID:11943179, PMID:21036907]. Within the TOM core it acts antagonistically to the stabilizing subunits Tom5 and Tom6: its loss stabilizes receptor–pore interactions among Tom20, Tom22, and Tom40 and impairs two-step import as well as outer-membrane porin biogenesis [PMID:8641278, PMID:21059357]. Tom7 also coordinates beta-barrel protein assembly by recruiting and sequestering free Mdm10, promoting its dissociation from the SAM/TOB complex to control the timing of Tom40 release and the late assembly of Tom22, thereby tuning the maturation of both Tom40 and porin [PMID:16760475, PMID:21036907, PMID:21059357]. In the regulation of mitochondrial quality control, Tom7 is specifically required to arrest PINK1 at the outer membrane upon depolarization, opposing OMA1-mediated PINK1 cleavage in a regulated balance that governs PINK1/Parkin-dependent mitophagy [PMID:30733118, PMID:bio_10.1101_2025.06.10.658840]. Biallelic loss-of-function variants in human TOMM7 cause an autosomal recessive progeroid syndrome and syndromic short stature accompanied by altered mitochondrial protein import and bioenergetic uncoupling [PMID:36282599, PMID:36299998].","teleology":[{"year":1996,"claim":"Established Tom7 as a TOM translocase subunit and, unexpectedly, as a destabilizing element whose loss tightens receptor–pore contacts and impairs import — defining a regulatory rather than purely structural role.","evidence":"Yeast deletion/double-mutant genetics, blue native PAGE, and in vitro import assays","pmids":["8641278"],"confidence":"High","gaps":["Did not resolve the direct molecular contacts of Tom7","Mechanism distinguishing Tom7 from the stabilizing Tom6 not defined at residue level"]},{"year":2001,"claim":"Demonstrated that Tom7 physically contacts Tom40 and assembles into authentic TOM complexes, anchoring its regulatory role to a direct interaction with the import pore.","evidence":"In vivo cross-linking and in vitro import/assembly assays in Neurospora crassa","pmids":["11278536"],"confidence":"High","gaps":["Which segment of Tom7 mediates Tom40 contact not yet mapped"]},{"year":2002,"claim":"Defined Tom7 as a tail-anchored protein whose C-terminal transmembrane segment, including a conserved proline, carries outer-membrane targeting information, and showed the human protein assembles via a Tom40-containing intermediate into the mature TOM complex.","evidence":"Truncation/proline mutagenesis with microscopy in yeast; HeLa mitochondrial import, BN-PAGE and antibody supershift for the human protein","pmids":["11943179","12198123"],"confidence":"Medium","gaps":["Single-lab targeting analysis","Rate-limiting role of Tom22 in human assembly not connected to Tom7's regulatory functions"]},{"year":2006,"claim":"Revealed that Tom7 acts antagonistically to Mdm10 in beta-barrel biogenesis, segregating Mdm10 from the SAM(holo) complex to selectively restrain Tom40 versus porin assembly.","evidence":"Yeast TOM7 deletion, BN-PAGE, in vitro assembly assays and co-immunoprecipitation","pmids":["16760475"],"confidence":"High","gaps":["Direct physical basis of Tom7–Mdm10 interaction not yet shown"]},{"year":2010,"claim":"Mapped Tom7's direct contacts to Tom40 (via its transmembrane segment) and Mdm10 by site-specific photocross-linking, and resolved two distinct inhibitory steps — early antagonism of Tom5/Tom6 and late promotion of SAM–Mdm10 dissociation delaying Tom22 assembly.","evidence":"Site-specific in vivo photocross-linking, depletion/overexpression, BN-PAGE and in vitro import in yeast","pmids":["21036907","21059357"],"confidence":"High","gaps":["Structural model of these transient assembly intermediates absent","How the two steps are temporally coordinated not defined"]},{"year":2018,"claim":"Linked Tom7 to vascular biology by showing its deficit increases mitochondrial Rac1 import and redox signaling, with endothelial rescue correcting cerebrovascular malformation.","evidence":"Zebrafish screen, conditional knockout mice, endothelial transgenic rescue and import assays","pmids":["30354240"],"confidence":"Medium","gaps":["Mechanism by which Tom7 restricts Rac1 import unresolved","Single lab; relation to canonical TOM regulatory role unclear"]},{"year":2019,"claim":"Identified Tom7 as the factor required to arrest PINK1 at the outer membrane upon depolarization, defining a regulated balance with OMA1 that gates PINK1/Parkin mitophagy.","evidence":"Tom7 knockout cells, PINK1 motif mutagenesis, OMA1 suppression and protease-protection assays","pmids":["30733118"],"confidence":"High","gaps":["Structural basis of how Tom7 retains PINK1 not resolved","Whether this uses the same Tom40 contacts as import regulation unknown"]},{"year":2022,"claim":"Connected biallelic TOMM7 loss-of-function to human disease — a progeroid syndrome and syndromic short stature — with patient cells and mouse models showing altered import and oxidation/ATP-synthesis uncoupling.","evidence":"Exome sequencing, mitochondrial proteomics and respirometry in patient fibroblasts; mouse knock-in/knockout bioenergetics","pmids":["36282599","36299998"],"confidence":"Medium","gaps":["No reconstitution or variant rescue in the progeroid family","Mechanistic link from import defect to bioenergetic uncoupling not established"]},{"year":2025,"claim":"Extended the mitophagy role to disease contexts, showing TOMM7 modulates PINK1/Parkin mitophagy in kidney tubular cells via PLA2G6 redistribution and in human dopaminergic neurons via ubiquitin pSer65, and is transcriptionally repressed by ZBTB12.","evidence":"Tomm7 overexpression in db/db mice, HK-2 cell assays, PLA2G6 fractionation, ChIP; CRISPR knockout in iPSC-derived dopaminergic neurons (preprint)","pmids":["41276015","bio_10.1101_2025.06.10.658840"],"confidence":"Medium","gaps":["Direct molecular link between Tom7 and PLA2G6 trafficking unclear","Neuronal data are preprint and single-lab","ZBTB12 regulation not connected to physiological mitophagy triggers"]},{"year":null,"claim":"How Tom7's single transmembrane contact with Tom40 simultaneously supports its destabilizing role in import, its Mdm10-dependent assembly regulation, and its PINK1 retention function remains unresolved at a structural and mechanistic level.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of Tom7 within the human TOM complex bound to PINK1","Whether import-regulatory and mitophagy-gating activities are separable not tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,6,4,5]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,3]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8,11,12]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,3]}],"complexes":["TOM complex"],"partners":["TOMM40","MDM10","TOMM22","PINK1","OMA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P0U1","full_name":"Mitochondrial import receptor subunit TOM7 homolog","aliases":["Translocase of outer membrane 7 kDa subunit homolog"],"length_aa":55,"mass_kda":6.2,"function":"Component of the translocase of the outer membrane of mitochondria (TOM) complex essential for the recognition and translocation of cytosolically synthesized mitochondrial preproteins (PubMed:40080546). The TOM complex associates with the ion channel VDAC2 and PINK1 kinase at depolarized mitochondria, this interaction stabilizes PINK1 at the outer mitochondrial membrane and triggers downstream mitophagy by the recruitment of the E3 ubiquitin ligase PRKN (PubMed:40080546)","subcellular_location":"Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/Q9P0U1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TOMM7","classification":"Not Classified","n_dependent_lines":26,"n_total_lines":1208,"dependency_fraction":0.02152317880794702},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TOMM20A","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/TOMM7","total_profiled":1310},"omim":[{"mim_id":"620601","title":"GARG-MISHRA PROGEROID SYNDROME; GMPGS","url":"https://www.omim.org/entry/620601"},{"mim_id":"616169","title":"TRANSLOCASE OF OUTER MITOCHONDRIAL MEMBRANE 5; TOMM5","url":"https://www.omim.org/entry/616169"},{"mim_id":"616168","title":"TRANSLOCASE OF OUTER MITOCHONDRIAL MEMBRANE 6; TOMM6","url":"https://www.omim.org/entry/616168"},{"mim_id":"608309","title":"PTEN-INDUCED KINASE 1; PINK1","url":"https://www.omim.org/entry/608309"},{"mim_id":"607980","title":"TRANSLOCASE OF OUTER MITOCHONDRIAL MEMBRANE 7; TOMM7","url":"https://www.omim.org/entry/607980"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TOMM7"},"hgnc":{"alias_symbol":["Tom7"],"prev_symbol":[]},"alphafold":{"accession":"Q9P0U1","domains":[{"cath_id":"-","chopping":"9-53","consensus_level":"high","plddt":94.5618,"start":9,"end":53}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0U1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0U1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0U1-F1-predicted_aligned_error_v6.png","plddt_mean":92.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TOMM7","jax_strain_url":"https://www.jax.org/strain/search?query=TOMM7"},"sequence":{"accession":"Q9P0U1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P0U1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P0U1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0U1"}},"corpus_meta":[{"pmid":"30733118","id":"PMC_30733118","title":"Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1.","date":"2019","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/30733118","citation_count":145,"is_preprint":false},{"pmid":"8641278","id":"PMC_8641278","title":"Tom7 modulates the dynamics of the mitochondrial outer membrane translocase and plays a pathway-related role in protein import.","date":"1996","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8641278","citation_count":137,"is_preprint":false},{"pmid":"12198123","id":"PMC_12198123","title":"Insertion and assembly of human tom7 into the preprotein translocase complex of the outer mitochondrial membrane.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12198123","citation_count":114,"is_preprint":false},{"pmid":"21036907","id":"PMC_21036907","title":"Tom7 regulates Mdm10-mediated assembly of the mitochondrial import channel protein Tom40.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21036907","citation_count":88,"is_preprint":false},{"pmid":"16760475","id":"PMC_16760475","title":"Mitochondrial protein sorting: differentiation of beta-barrel assembly by Tom7-mediated segregation of Mdm10.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16760475","citation_count":87,"is_preprint":false},{"pmid":"21059357","id":"PMC_21059357","title":"Biogenesis of mitochondria: dual role of Tom7 in modulating assembly of the preprotein translocase of the outer membrane.","date":"2010","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21059357","citation_count":76,"is_preprint":false},{"pmid":"11278536","id":"PMC_11278536","title":"Assembly of Tom6 and Tom7 into the TOM core complex of Neurospora crassa.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11278536","citation_count":55,"is_preprint":false},{"pmid":"11943179","id":"PMC_11943179","title":"A conserved proline residue is present in the transmembrane-spanning domain of Tom7 and other tail-anchored protein subunits of the TOM translocase.","date":"2002","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/11943179","citation_count":42,"is_preprint":false},{"pmid":"36282599","id":"PMC_36282599","title":"Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.","date":"2022","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/36282599","citation_count":24,"is_preprint":false},{"pmid":"30354240","id":"PMC_30354240","title":"Endothelial Mitochondrial Preprotein Translocase Tomm7-Rac1 Signaling Axis Dominates Cerebrovascular Network Homeostasis.","date":"2018","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/30354240","citation_count":18,"is_preprint":false},{"pmid":"36299998","id":"PMC_36299998","title":"A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.","date":"2022","source":"HGG advances","url":"https://pubmed.ncbi.nlm.nih.gov/36299998","citation_count":16,"is_preprint":false},{"pmid":"30468788","id":"PMC_30468788","title":"TOM7 silencing exacerbates focal cerebral ischemia injury in rat by targeting PINK1/Beclin1-mediated autophagy.","date":"2018","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/30468788","citation_count":12,"is_preprint":false},{"pmid":"41276015","id":"PMC_41276015","title":"Mitochondrial protein TOMM7 alleviates diabetic kidney disease by regulating mitophagy via intracellular redistribution of phospholipase PLA2G6.","date":"2025","source":"Kidney 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Yi xue ban = Journal of Central South University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25652373","citation_count":3,"is_preprint":false},{"pmid":"41540546","id":"PMC_41540546","title":"Single-cell and Bulk RNA-Seq Analyses Reveal TOMM7-mediated Multi-cell Death Mechanisms Driving Muscle-invasive Bladder Cancer Progression.","date":"2026","source":"Recent patents on anti-cancer drug discovery","url":"https://pubmed.ncbi.nlm.nih.gov/41540546","citation_count":0,"is_preprint":false},{"pmid":"15759864","id":"PMC_15759864","title":"Cloning and characterization of TOM7-like gene in wheat.","date":"2005","source":"Yi chuan xue bao = Acta genetica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/15759864","citation_count":0,"is_preprint":false},{"pmid":"41460760","id":"PMC_41460760","title":"Growth Hormone Response in a Child With a Homozygous TOMM7 Mutation: Novel Therapeutic Insights.","date":"2025","source":"The American journal of case reports","url":"https://pubmed.ncbi.nlm.nih.gov/41460760","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.10.658840","title":"A CRISPR-CAS9 high throughput machine-learning platform for modulation of genes involved in Parkinson’s disease-associated PINK1-mitophagy in iPSC-derived dopaminergic neurons","date":"2025-06-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.10.658840","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.27.600933","title":"A genome-wide association study of high-sensitivity C-reactive protein in a large Korean population highlights its role in cholesterol metabolism","date":"2024-06-28","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.27.600933","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11343,"output_tokens":3614,"usd":0.044119,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11449,"output_tokens":3316,"usd":0.070072,"stage2_stop_reason":"end_turn"},"total_usd":0.114191,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"Tom7 is an integral membrane subunit of the mitochondrial outer membrane TOM translocase. Deletion of TOM7 inhibits import of the outer membrane protein porin and strongly impairs two-step preprotein import into the mitochondrial interior. Loss of Tom7 stabilizes interactions between receptors Tom20 and Tom22 and the import pore Tom40, indicating Tom7 exerts a destabilizing effect on part of the outer membrane translocase, while Tom6 stabilizes these interactions. Genetic synthetic growth defects of tom7Δ tom20Δ and tom7Δ tom6Δ double mutants confirmed functional relationships between Tom7, Tom20, and Tom6.\",\n      \"method\": \"Yeast genetics (deletion mutants, double mutants), blue native PAGE, import assays in vitro, biochemical fractionation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic epistasis, biochemical fractionation, import assays), foundational study replicated by subsequent work\",\n      \"pmids\": [\"8641278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Tom6 and Tom7 are subunits of the Neurospora crassa TOM core complex. Cross-linking experiments showed both proteins are in direct contact with Tom40. Precursors of Tom6 and Tom7 insert into the outer membrane in vitro and assemble into authentic TOM complexes; assembly shares a common binding site with the general import pathway and requires the integrity of TOM receptor components.\",\n      \"method\": \"Cross-linking in vivo, in vitro import/assembly assays, blue native PAGE, hybrid protein analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct cross-linking demonstrating physical contact, in vitro reconstitution of assembly, multiple orthogonal methods\",\n      \"pmids\": [\"11278536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Tom7 is a tail-anchored protein; the carboxy-terminal 33 amino acids contain the targeting information for the mitochondrial outer membrane. A conserved proline residue within the transmembrane segment is required for efficient targeting of Tom7 to the outer membrane. An equivalent proline residue is important for targeting each of the other three tail-anchored proteins (Tom5, Tom6, Tom22) that associate with Tom40 to form the TOM core.\",\n      \"method\": \"Deletion/truncation analysis, mutagenesis of conserved proline, fluorescence microscopy, import assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus import assays, single lab, two complementary methods\",\n      \"pmids\": [\"11943179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Human TOMM7 is imported into mitochondria in a nucleotide-independent manner and is anchored to the outer membrane with its C terminus facing the intermembrane space. Human Tom7 assembles first into an ~120 kDa import intermediate containing Tom40 but lacking receptor components, which is then chased to the stable ~380 kDa TOM complex additionally containing Tom22. Tom22 is rate-limiting for TOM complex formation, as Tom22 overexpression accelerates Tom7 assembly into the 380 kDa complex.\",\n      \"method\": \"Import assays in HeLa cell mitochondria, blue native PAGE, supershift analysis with TOM-specific antibodies, Tom22 overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical methods (import, BN-PAGE, antibody supershift), characterization of human protein assembly pathway\",\n      \"pmids\": [\"12198123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Tom7 functions in an antagonistic manner to Mdm10 in beta-barrel protein biogenesis. Tom7 promotes segregation of Mdm10 from the SAM(holo) complex into a low molecular mass form. Upon deletion of Tom7, the fraction of Mdm10 in the SAM(holo) complex is significantly increased, selectively promoting Tom40 assembly but not porin assembly.\",\n      \"method\": \"Yeast genetics (TOM7 deletion), blue native PAGE, in vitro import/assembly assays, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic deletion combined with biochemical reconstitution and BN-PAGE, replicated by subsequent studies from other labs\",\n      \"pmids\": [\"16760475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Tom7 directly interacts with Tom40 through its transmembrane segment and with Mdm10, as shown by site-specific photocross-linking in vivo. Tom7 recruits Mdm10 and enhances its association with the MMM1 complex, thereby regulating the timing of Tom40 release from the TOB/SAM complex for subsequent assembly into the TOM40 complex. Depletion of Tom7 decreased transient accumulation of Tom40 at the TOB complex, while overexpression of Tom7 enhanced it.\",\n      \"method\": \"Site-specific photocross-linking in vivo, in vitro import assays, BN-PAGE, Tom7 depletion and overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site-specific photocross-linking identifying direct contacts, combined with functional gain/loss-of-function assays\",\n      \"pmids\": [\"21036907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Tom7 plays an inhibitory role at two distinct steps in TOM complex biogenesis: (1) Tom7 acts antagonistically to Tom5 and Tom6 at an early stage of Tom40 assembly at the SAM complex; (2) Tom7 interacts with free Mdm10 (not bound to the SAM complex), thereby promoting dissociation of the SAM-Mdm10 complex and delaying Tom22 assembly with Tom40 at a late stage. Thus Tom7 modulates biogenesis of both the beta-barrel protein Tom40 and the alpha-helical Tom22.\",\n      \"method\": \"Yeast genetics, blue native PAGE, in vitro import assays, co-immunoprecipitation\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, complementary to parallel study (PMID 21036907), identifies two mechanistically distinct inhibitory steps\",\n      \"pmids\": [\"21059357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Tomm7 deficit in endothelial cells induces increased import of Rac1 protein into mitochondria and facilitates mitochondrial Rac1-coupled redox signaling, causing angiogenic impairment that underlies cerebrovascular network malformation. Endothelial-specific transgenesis of tomm7 restored cerebrovascular anomalies in Tomm7-knockout mice.\",\n      \"method\": \"Loss-of-function genetic screening in zebrafish, conditional knockout mice, endothelial-specific transgenesis, vascular imaging, mitochondrial protein import assays\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiment in two model organisms with mechanistic follow-up on Rac1 import, single lab\",\n      \"pmids\": [\"30354240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tom7 is required for PINK1 accumulation at the outer mitochondrial membrane upon mitochondrial depolarization. Deletion of Tom7 allows PINK1 to be imported into depolarized mitochondria where it is cleaved by the OMA1 protease rather than arrested at the outer membrane. PINK1 contains a negatively charged amino acid cluster motif C-terminal to its transmembrane domain that is required for import arrest; mutagenesis of this motif phenocopies Tom7 deletion. Thus, ΔΨm-loss-dependent PINK1 import arrest involves an actively regulated 'tug of war' between Tom7 (promoting outer membrane retention) and OMA1 (promoting PINK1 cleavage after inner-membrane import).\",\n      \"method\": \"Tom7 knockout cell lines, PINK1 mutagenesis, OMA1 suppression, import assays, protease protection assays, cell biology\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic deletion, site-directed mutagenesis, protease cleavage assays, epistasis with OMA1, multiple orthogonal methods in one study\",\n      \"pmids\": [\"30733118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A homozygous missense variant in TOMM7 (p.Pro29Leu) causes an autosomal recessive progeroid syndrome in a human patient. Proteomic comparison of mitochondria from patient-derived fibroblasts vs. controls revealed increased abundance of oxidative phosphorylation proteins and reduced abundance of phospholipid metabolism proteins, along with elevated basal and maximal oxygen consumption rates, consistent with altered mitochondrial protein import due to biallelic loss-of-function TOMM7.\",\n      \"method\": \"Exome sequencing, mitochondrial proteomics (quantitative MS), oxygen consumption rate measurement in patient-derived fibroblasts\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic and bioenergetic profiling of patient cells, single family, no reconstitution or rescue experiment\",\n      \"pmids\": [\"36282599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A homozygous hypomorphic variant in TOMM7 (p.Trp25Arg) causes syndromic short stature with mitochondrial dysfunction. Mouse models homozygous for this variant show a milder phenotype than complete Tomm7 deletion mice. Tomm7 deficiency causes an uncoupling between oxidation and ATP synthesis without impairing the ETC or tricarboxylic acid cycle function, as evidenced by increased oxygen consumption with normal responses to ETC inhibitors.\",\n      \"method\": \"Mouse knock-in and knockout models, oxygen consumption assays, ETC inhibitor assays, patient variant analysis\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comparative mouse models (hypomorph vs. full KO), functional bioenergetics, single lab\",\n      \"pmids\": [\"36299998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TOMM7 regulates PINK1/Parkin-mediated mitophagy in kidney tubular cells by modulating the intracellular redistribution of phospholipase PLA2G6 between the nucleus and mitochondria. Tomm7 overexpression in db/db mice restored PINK1/Parkin-mediated mitophagy and alleviated kidney injury. ZBTB12 was identified as a transcriptional repressor of TOMM7.\",\n      \"method\": \"Tomm7 overexpression in db/db mice, HK-2 cell overexpression/knockdown, mitophagy flux assays, subcellular fractionation of PLA2G6, ChIP/transcription factor binding assays\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo rescue with mechanistic follow-up on PLA2G6 redistribution, single lab\",\n      \"pmids\": [\"41276015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CRISPR-Cas9 knockout of TOM7 in iPSC-derived dopaminergic neurons decreased ubiquitin pSer65 upregulation during mitophagy activation (induced by exogenous stimuli), confirming TOM7's role in the PINK1-PARKIN mitophagy pathway in a human neuronal model.\",\n      \"method\": \"High-throughput arrayed CRISPR-Cas9 KO screen in iPSC-derived dopaminergic neurons, high-content immunofluorescence imaging, machine learning analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with quantitative phenotypic readout in disease-relevant human cell model, preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.06.10.658840\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TOMM7 encodes a small tail-anchored integral membrane subunit of the TOM translocase of the outer mitochondrial membrane that plays a dynamic regulatory role: it destabilizes TOM receptor–pore interactions to modulate preprotein translocation, directly contacts Tom40 via its transmembrane segment, sequesters Mdm10 away from the SAM/TOB complex to differentially regulate beta-barrel protein assembly (promoting porin but inhibiting Tom40 maturation timing), and is specifically required for arrest of PINK1 at the outer membrane upon mitochondrial depolarization by opposing OMA1-mediated PINK1 cleavage—thereby controlling PINK1/Parkin-dependent mitophagy; loss-of-function variants cause a human progeroid syndrome with mitochondrial import defects.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TOMM7 encodes a small tail-anchored integral membrane subunit of the TOM translocase of the mitochondrial outer membrane that exerts a dynamic, predominantly destabilizing regulatory influence on preprotein import [#0]. Anchored in the outer membrane via a C-terminal transmembrane segment whose conserved proline is required for targeting, Tom7 makes direct contact with the import pore Tom40 [#1, #2, #5]. Within the TOM core it acts antagonistically to the stabilizing subunits Tom5 and Tom6: its loss stabilizes receptor–pore interactions among Tom20, Tom22, and Tom40 and impairs two-step import as well as outer-membrane porin biogenesis [#0, #6]. Tom7 also coordinates beta-barrel protein assembly by recruiting and sequestering free Mdm10, promoting its dissociation from the SAM/TOB complex to control the timing of Tom40 release and the late assembly of Tom22, thereby tuning the maturation of both Tom40 and porin [#4, #5, #6]. In the regulation of mitochondrial quality control, Tom7 is specifically required to arrest PINK1 at the outer membrane upon depolarization, opposing OMA1-mediated PINK1 cleavage in a regulated balance that governs PINK1/Parkin-dependent mitophagy [#8, #12]. Biallelic loss-of-function variants in human TOMM7 cause an autosomal recessive progeroid syndrome and syndromic short stature accompanied by altered mitochondrial protein import and bioenergetic uncoupling [#9, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established Tom7 as a TOM translocase subunit and, unexpectedly, as a destabilizing element whose loss tightens receptor–pore contacts and impairs import — defining a regulatory rather than purely structural role.\",\n      \"evidence\": \"Yeast deletion/double-mutant genetics, blue native PAGE, and in vitro import assays\",\n      \"pmids\": [\"8641278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the direct molecular contacts of Tom7\", \"Mechanism distinguishing Tom7 from the stabilizing Tom6 not defined at residue level\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated that Tom7 physically contacts Tom40 and assembles into authentic TOM complexes, anchoring its regulatory role to a direct interaction with the import pore.\",\n      \"evidence\": \"In vivo cross-linking and in vitro import/assembly assays in Neurospora crassa\",\n      \"pmids\": [\"11278536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which segment of Tom7 mediates Tom40 contact not yet mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined Tom7 as a tail-anchored protein whose C-terminal transmembrane segment, including a conserved proline, carries outer-membrane targeting information, and showed the human protein assembles via a Tom40-containing intermediate into the mature TOM complex.\",\n      \"evidence\": \"Truncation/proline mutagenesis with microscopy in yeast; HeLa mitochondrial import, BN-PAGE and antibody supershift for the human protein\",\n      \"pmids\": [\"11943179\", \"12198123\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab targeting analysis\", \"Rate-limiting role of Tom22 in human assembly not connected to Tom7's regulatory functions\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed that Tom7 acts antagonistically to Mdm10 in beta-barrel biogenesis, segregating Mdm10 from the SAM(holo) complex to selectively restrain Tom40 versus porin assembly.\",\n      \"evidence\": \"Yeast TOM7 deletion, BN-PAGE, in vitro assembly assays and co-immunoprecipitation\",\n      \"pmids\": [\"16760475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical basis of Tom7–Mdm10 interaction not yet shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapped Tom7's direct contacts to Tom40 (via its transmembrane segment) and Mdm10 by site-specific photocross-linking, and resolved two distinct inhibitory steps — early antagonism of Tom5/Tom6 and late promotion of SAM–Mdm10 dissociation delaying Tom22 assembly.\",\n      \"evidence\": \"Site-specific in vivo photocross-linking, depletion/overexpression, BN-PAGE and in vitro import in yeast\",\n      \"pmids\": [\"21036907\", \"21059357\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of these transient assembly intermediates absent\", \"How the two steps are temporally coordinated not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked Tom7 to vascular biology by showing its deficit increases mitochondrial Rac1 import and redox signaling, with endothelial rescue correcting cerebrovascular malformation.\",\n      \"evidence\": \"Zebrafish screen, conditional knockout mice, endothelial transgenic rescue and import assays\",\n      \"pmids\": [\"30354240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Tom7 restricts Rac1 import unresolved\", \"Single lab; relation to canonical TOM regulatory role unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified Tom7 as the factor required to arrest PINK1 at the outer membrane upon depolarization, defining a regulated balance with OMA1 that gates PINK1/Parkin mitophagy.\",\n      \"evidence\": \"Tom7 knockout cells, PINK1 motif mutagenesis, OMA1 suppression and protease-protection assays\",\n      \"pmids\": [\"30733118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how Tom7 retains PINK1 not resolved\", \"Whether this uses the same Tom40 contacts as import regulation unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected biallelic TOMM7 loss-of-function to human disease — a progeroid syndrome and syndromic short stature — with patient cells and mouse models showing altered import and oxidation/ATP-synthesis uncoupling.\",\n      \"evidence\": \"Exome sequencing, mitochondrial proteomics and respirometry in patient fibroblasts; mouse knock-in/knockout bioenergetics\",\n      \"pmids\": [\"36282599\", \"36299998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstitution or variant rescue in the progeroid family\", \"Mechanistic link from import defect to bioenergetic uncoupling not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the mitophagy role to disease contexts, showing TOMM7 modulates PINK1/Parkin mitophagy in kidney tubular cells via PLA2G6 redistribution and in human dopaminergic neurons via ubiquitin pSer65, and is transcriptionally repressed by ZBTB12.\",\n      \"evidence\": \"Tomm7 overexpression in db/db mice, HK-2 cell assays, PLA2G6 fractionation, ChIP; CRISPR knockout in iPSC-derived dopaminergic neurons (preprint)\",\n      \"pmids\": [\"41276015\", \"bio_10.1101_2025.06.10.658840\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between Tom7 and PLA2G6 trafficking unclear\", \"Neuronal data are preprint and single-lab\", \"ZBTB12 regulation not connected to physiological mitophagy triggers\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Tom7's single transmembrane contact with Tom40 simultaneously supports its destabilizing role in import, its Mdm10-dependent assembly regulation, and its PINK1 retention function remains unresolved at a structural and mechanistic level.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of Tom7 within the human TOM complex bound to PINK1\", \"Whether import-regulatory and mitophagy-gating activities are separable not tested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 6, 4, 5]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005741\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8, 11, 12]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [\"TOM complex\"],\n    \"partners\": [\"TOMM40\", \"MDM10\", \"TOMM22\", \"PINK1\", \"OMA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}