{"gene":"TOMM22","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1999,"finding":"Tom22 is a multifunctional organizer of the TOM complex: its single transmembrane domain stabilizes interactions between core TOM subcomplexes, while its cytosolic domain serves as a docking point for peripheral receptors Tom20 and Tom70. In the absence of Tom22, the translocase dissociates into core complexes and loses tight channel gating control.","method":"Genetic deletion of Tom22 in yeast combined with biochemical analysis of TOM complex assembly and channel gating","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with multiple defined biochemical phenotypes (complex dissociation, channel gating defects, receptor docking), replicated across multiple experimental approaches","pmids":["10519552"],"is_preprint":false},{"year":1997,"finding":"The purified cytosolic domain of Tom22 selectively recognizes presequence-carrying preproteins in a salt-sensitive manner, functioning as a presequence receptor distinct from Tom20 and Tom70.","method":"In vitro binding assays with purified recombinant cytosolic domains of Tom20, Tom22, and Tom70 against mitochondrial preproteins; competition with synthetic presequence peptides","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro reconstitution with purified proteins, multiple substrate tests, competition assays","pmids":["9252394"],"is_preprint":false},{"year":1999,"finding":"Tom22 cytosolic domain binds to segments corresponding to the carboxyl-terminal part of the presequence and the amino-terminal part of the mature protein of presequence-carrying preproteins (CoxIV), but does not efficiently bind multiple segments of the non-cleavable phosphate carrier.","method":"Binding of purified cytosolic receptor domains to cellulose-bound peptide scans (13-mer peptide libraries) derived from CoxIV and phosphate carrier","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic in vitro peptide-scan binding with purified protein, multiple substrates tested","pmids":["10347216"],"is_preprint":false},{"year":1997,"finding":"The intermembrane space (IMS) domain of Tom22 functions as a trans binding site for preproteins with N-terminal targeting sequences during outer membrane translocation, consistent with the acid chain hypothesis; this function becomes essential when cytosolic receptor domains are removed or during two-step import.","method":"Import assays using yeast mutant mitochondria lacking the IMS domain of Tom22; two-step import protocol (accumulation without ΔΨ then import after ΔΨ restoration); removal of cytosolic receptor domains","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic and biochemical approaches in yeast, consistent with replicated findings across labs","pmids":["9343421"],"is_preprint":false},{"year":2001,"finding":"Tom40 and Tom22 form a highly stable core unit (GIP complex) that retains accumulated preproteins and exhibits characteristic TOM channel activity with two coupled conductance states; the GIP complex is resistant to urea and alkaline pH, and preprotein retention is not dependent on ionic interactions.","method":"Blue native PAGE, urea/salt/detergent treatment of isolated TOM complexes, electrophysiology of purified GIP complex from outer membrane vesicles","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution of channel activity, multiple biochemical dissection methods, electrophysiology","pmids":["11259583"],"is_preprint":false},{"year":2006,"finding":"TOM22 functions as a mitochondrial receptor for the pro-apoptotic protein Bax; the interaction involves the first alpha helix of Bax and two central alpha helices. Knockdown of TOM22 inhibits Bax association with mitochondria and prevents Bax-dependent apoptosis.","method":"Bacterial two-hybrid assay, crosslinking strategies, peptide mapping, antisense knockdown of TOM22, yeast haploid strain with reduced TOM22","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (two-hybrid, crosslinking, peptide mapping, KD with functional readout), consistent findings","pmids":["17096026"],"is_preprint":false},{"year":2007,"finding":"Tom20 and Tom22 are involved in the same step or sequential steps along the same pathway for targeting signal recognition during mitochondrial protein import; deletion of their receptor domains has similar effects across diverse import substrates.","method":"In vitro cleavage of receptor domains via introduced TEV protease sites in yeast; import assays of multiple mitochondrial precursor proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic in organello domain-deletion approach with multiple substrates across different import pathways","pmids":["18063580"],"is_preprint":false},{"year":2011,"finding":"The cytosolic receptor domain of Tom22 accepts substrate precursor proteins, and the IMS domain of Tom22 transfers them to Tim50 of the inner-membrane translocator TIM23 complex, as mapped at single amino acid residue resolution in vivo.","method":"In vivo and in organello site-specific photocrosslinking; changes in crosslinking patterns induced by excess substrate or presequence peptides","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific photocrosslinking at residue-level resolution both in vivo and in organello, functional perturbation controls","pmids":["21896724"],"is_preprint":false},{"year":2013,"finding":"CK2 constitutively phosphorylates the cytosolic precursor of Tom22 at Ser44 and Ser46, promoting its import into the TOM complex. CK1 (bound to mitochondria) phosphorylates Tom22 at Thr57 and stimulates assembly of Tom22 and Tom20. PKA phosphorylates the precursor of Tom22 at Thr76 and impairs its import, acting oppositely to CK1 and CK2.","method":"In vitro kinase assays, phosphorylation site mapping by mass spectrometry, import assays with phosphomimetic/phospho-null mutants, glucose-stimulated signaling experiments in yeast","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro kinase assays with site mapping, multiple kinases tested, import functional readout, multiple orthogonal methods","pmids":["24093680"],"is_preprint":false},{"year":2000,"finding":"Human TOM22 (hTom22) forms a complex with Tom20, functions as an import receptor via its cytosolic domain, and complements Δtom22 yeast cells; the C-terminal segment of the cytosolic domain is important for presequence binding, the N-terminal domain binds the mature portion of preproteins, and an internal segment of the cytosolic domain mediates interaction with Tom20.","method":"Immunoprecipitation, import inhibition assay with deletion mutants, cell-free binding studies, complementation of yeast Δtom22","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple domain-mapping experiments with defined deletion mutants, complementation assay, binding studies","pmids":["10982837"],"is_preprint":false},{"year":2000,"finding":"Mammalian TOM22 (1C9-2) is stably associated with TOM40 in an ~400 kDa complex at the mitochondrial outer membrane and functionally complements Δtom22 yeast cells for growth and mitochondrial protein import.","method":"Immunopurification, blue native PAGE, import inhibition with antibodies, complementation of yeast Δtom22","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical complex identification, import inhibition, yeast complementation — multiple orthogonal methods","pmids":["10900208"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structure of human TOM core complex at 2.53 Å, and TOM complex with Tom22 and Tom20 cytosolic domains at 3.74 Å, reveals that Tom20 and Tom22 share a similar three-helix bundle structural feature in their cytosolic domains. Structure-guided mutagenesis shows the Tom22 cytosolic domain is responsible for presequence binding, with helix H1 being critical.","method":"Cryo-EM structure determination, structure-guided mutagenesis, biochemical binding assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure combined with mutagenesis and biochemical validation","pmids":["35733257"],"is_preprint":false},{"year":2018,"finding":"In mammalian skeletal muscle, CSNK2/CK2-mediated phosphorylation of TOMM22 controls mitophagy: loss of CSNK2 reduces TOMM22 phosphorylation and its binding affinity for mitochondrial precursor proteins, leading to PINK1 accumulation and mitophagy. Phosphomimetic TOMM22 rescues oxygen consumption rate and normalizes mitophagy in Csnk2b-KO muscle.","method":"Skeletal muscle-specific Csnk2b conditional knockout mouse, in vitro phosphorylation assays with muscle lysates, electron microscopy for autophagosomes, electroporation of phosphomimetic Tomm22 in vivo, oxygen consumption rate measurement","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic KO model plus in vitro phosphorylation assay, functional rescue with phosphomimetic, multiple phenotypic readouts","pmids":["29165030"],"is_preprint":false},{"year":2019,"finding":"Porin (Por1) acts as a sink to bind newly imported Tom22, modulating its integration into the trimeric TOM complex. Por1 sequestration of Tom22 dissociated from the trimeric TOM complex enhances the dimeric TOM complex (lacking Tom22), which is preferable for import of TIM40/MIA-dependent proteins. Por1 also contributes to cell-cycle-dependent variation of the functional trimeric TOM complex.","method":"Co-immunoprecipitation, blue native PAGE, genetic analysis, cell-cycle synchronization experiments in yeast","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, BN-PAGE complex analysis, genetic manipulation, multiple functional readouts in yeast","pmids":["30738703"],"is_preprint":false},{"year":1998,"finding":"A short segment of the cytosolic domain of Neurospora TOM22 contains a novel internal import signal with a net positive charge that is essential for targeting and assembly of TOM22 into the outer membrane; the transmembrane segment and IMS domain alone are insufficient for import.","method":"In vitro import studies with TOM22 deletion and charge-reversal mutants in Neurospora","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis with in vitro import readout, single lab","pmids":["9565567"],"is_preprint":false},{"year":1998,"finding":"An abundance of negative charges in the cytosolic domain of Neurospora TOM22 is not essential for preprotein binding or import; however, other structural features of this domain are required (deletion of the entire region abolishes function).","method":"Systematic charge-neutralization mutagenesis of the cytosolic domain, mitochondrial import assays, precursor binding assays with outer membrane vesicles, complementation in heterokaryon","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis with multiple functional readouts, but single lab, result is primarily negative (charges not essential)","pmids":["9584158"],"is_preprint":false},{"year":2004,"finding":"Rat TOM22 targeting to the mitochondrial outer membrane and assembly into the TOM complex requires three structural elements: an acidic alpha-helical cytoplasmic import sequence ~30 residues upstream of the TMD, the TMD with appropriate hydrophobicity, and a 20-residue C-terminal IMS segment. The import sequence interacts intramolecularly with TMD and C-tail, and also with Tom20 by yeast two-hybrid.","method":"Systematic deletion/mutation analysis in HeLa cells with confocal microscopy, cell fractionation, blue native PAGE, yeast two-hybrid","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis in mammalian cells with multiple readouts, two-hybrid for interaction, single lab","pmids":["14985332"],"is_preprint":false},{"year":2003,"finding":"The cytosolic domain of Tom22 has chaperone-like activity, preventing substrate proteins (e.g., citrate synthase) from aggregating. This activity is inhibited by presequence peptide, suggesting the presequence binding site and the chaperone active site are identical or overlapping.","method":"In vitro aggregation suppression assays with purified cytosolic domains of Tom20 and Tom22; competition with presequence peptide","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct in vitro biochemical assay with purified proteins, but single lab and single substrate tested","pmids":["14699115"],"is_preprint":false},{"year":2010,"finding":"NMR studies of plant ScTom22 show it binds presequences; AtTom22 (plant) does not bind presequences but instead binds to the AtTom20 receptor at the same site as presequences, suggesting it competes with presequences to enable their progression along the import pathway.","method":"NMR spectroscopy of cytosolic domains of AtTom20, AtTom22, and ScTom22 with presequence peptides","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — NMR structural/interaction data, but single lab, involves plant orthologs","pmids":["21087612"],"is_preprint":false},{"year":2017,"finding":"Mitochondrial inner-membrane AAA protease Yme1 degrades outer-membrane Tom22 via its adaptor proteins Mgr1 and Mgr3, which recognize the IMS domain of Tom22; the ATPase activity of Yme1 can dislocate the cytoplasmic domain of substrates into the IMS for proteolysis.","method":"Immunoprecipitation, in vivo site-specific photocrosslinking to map Mgr1/Mgr3 interactions with Tom22 IMS domain, ATPase-mutant Yme1 analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal immunoprecipitation plus site-specific photocrosslinking with mechanistic mutants, two orthogonal methods","pmids":["29138251"],"is_preprint":false},{"year":2018,"finding":"TOMM22 is the main mitochondrial receptor for amyloid-β (Aβ) peptides in yeast mitochondria; residues 25-42 of Aβ mediate the specific interaction with TOMM22. Aβ is then proposed to be transferred to TOMM40 and transported through the TOM channel.","method":"Yeast genetics (tom22 deletion), direct binding assays with Aβ peptide fragments, mitochondrial import assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and biochemical evidence in yeast, but single lab and some mechanistic steps remain proposed","pmids":["29925587"],"is_preprint":false},{"year":2016,"finding":"Tom22 is essential for steroidogenesis: Tom22 knockdown abolishes progesterone conversion in steroidogenic cells, and Tom22 forms a ~500 kDa complex with 3βHSD2 at the mitochondrial outer membrane. The IMS C-terminal segment of Tom22 interacts with a specific region of 3βHSD2. Tom22 absence inhibits 3βHSD2 expression but not import of CYP450scc or aldosterone synthase.","method":"siRNA knockdown, blue native PAGE, electron microscopy for localization, co-immunoprecipitation, steroidogenesis functional assays in MA-10 and NCI cells","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, BN-PAGE, EM localization, siRNA with functional readout, single lab","pmids":["26787839"],"is_preprint":false},{"year":2021,"finding":"Tom22, aldosterone synthase (P450c11AS), and intramitochondrial 30-kDa StAR form a 110-kDa trimolecular complex required for aldosterone synthesis in the rat heart, as demonstrated by protein crosslinking and co-immunoprecipitation.","method":"Blue native PAGE, immunoblotting, protein crosslinking, co-immunoprecipitation, mass spectrometry","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods (crosslinking, Co-IP, BN-PAGE, MS) in single lab","pmids":["33526603"],"is_preprint":false},{"year":2011,"finding":"Human Tom22 cytosolic domain expression in yeast increases Bax mitochondrial localization but decreases the proportion of active Bax and interferes with Bax oligomerization, suggesting the cytosolic domain of Tom22 promotes a membrane-competent but non-oligomeric Bax conformation.","method":"Co-immunoprecipitation, blue native PAGE, yeast expression system with human Bax","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and BN-PAGE in yeast expression system, single lab, two methods","pmids":["22198199"],"is_preprint":false},{"year":2024,"finding":"Tom22 stimulates Bax membrane insertion in a cell-free nanodisc system: Tom22 recognizes the GALLL hydrophobic motif in Bax helix α1, triggering conformational changes that lead to extrusion and membrane insertion of the C-terminal hydrophobic Hα9. Tom22-activated Bax forms ~5-nm pores in nanodiscs. D154Y and T174P mutations in Bax impair this Tom22-dependent mechanism.","method":"Cell-free synthesis with nanodiscs, liposome permeabilization assay, mutagenesis of Bax","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with nanodiscs and mutagenesis, but single lab","pmids":["39043635"],"is_preprint":false},{"year":2025,"finding":"Molecular dynamics simulations reveal that Tom22 helices undergo large motions coupled to global structural rearrangements in the TOM complex, particularly with the α2 helix within the Tom40 pore, and restraining Tom22 helices reduces ion permeability, linking Tom22 receptor dynamics to pore gating.","method":"All-atom molecular dynamics simulations (microsecond-scale) with and without restraints on Tom22 helices; ion permeability measurements in silico","journal":"Journal of chemical information and modeling","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational simulation only, no direct experimental validation in this paper","pmids":["41172152"],"is_preprint":false},{"year":2019,"finding":"Tom22 interacts with Mfn1 and modulates mitochondrial fusion: Tom22 deletion reduces mitochondrial fusion, ATP production, and increases apoptosis in endothelial cells; Tom22 overexpression restores mitochondrial dynamics and OXPHOS impaired by high glucose.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression in HUVECs, mitochondrial morphology imaging, ATP measurement","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for interaction, KD and OE with functional readouts, single lab","pmids":["31236191"],"is_preprint":false},{"year":2016,"finding":"Mitochondrial BKCa channel interacts with Tom22 via its transmembrane domain, and the BKCa 50-amino-acid DEC splice insert facilitates interaction with ANT but not Tom22. BKCa and Tom22 co-immunoprecipitate and co-segregate into mitochondrial fractions.","method":"Directed proteomics, co-immunoprecipitation, cell fractionation in HEK293T cells","journal":"Mitochondrion","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, single lab, limited mechanistic follow-up","pmids":["27592226"],"is_preprint":false},{"year":2009,"finding":"Certain cytochrome P450 proteins with chimeric mitochondrial targeting signals (CYP+33/1A1, CYP2B1) can bypass TOM20, TOM22, and TOM70 for translocation through TOM40, while others (CYP+5/1A1, CYP2E1) bypass TOM20 and TOM22 but require TOM70. This bypass occurs when CYP proteins interact sequentially with both Hsp70 and Hsp90.","method":"Antibody inhibition of specific TOM subunits, import assays, co-immunoprecipitation with chaperones","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple import pathway experiments with antibody inhibition and chaperone co-IP, single lab","pmids":["19401463","18480056"],"is_preprint":false},{"year":2024,"finding":"TOMM22 overexpression in pancreatic cancer cells increases import of mitochondrial proteins associated with respiration, RCI activity, NAD+/NADH ratio, oxygen consumption rate, membrane potential, and ATP production. TOMM22 silencing decreases these and suppresses malignant growth, placing TOMM22 upstream of mitochondrial respiratory function.","method":"TOMM22 siRNA knockdown and overexpression in pancreatic cancer cell lines, mitochondrial protein import assays, RCI activity measurement, Seahorse metabolic analysis","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and OE with multiple functional readouts including import assays, single lab","pmids":["37878010"],"is_preprint":false},{"year":2026,"finding":"BTN3A3 interacts with TOMM22 at mitochondria (identified by mass spectrometry and Co-IP); sorafenib stress promotes BTN3A3 mitochondrial translocation where it shields TOMM22 from ubiquitin-proteasome-dependent degradation. BTN3A3 deficiency leads to TOMM22 depletion, mitochondrial fragmentation, and impaired OXPHOS.","method":"Mass spectrometry, co-immunoprecipitation, ubiquitination assays, TOMM22 knockdown/rescue, live-cell imaging of BTN3A3 translocation, in vivo xenograft","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP, ubiquitination assay, rescue experiments, single lab","pmids":["42069175"],"is_preprint":false}],"current_model":"TOMM22 (Tom22) is the central receptor and organizer of the mitochondrial outer membrane TOM complex: its cytosolic domain binds presequence-carrying preproteins (via a three-helix bundle, with helix H1 critical) and docks peripheral receptors Tom20 and Tom70; its single transmembrane domain stabilizes interactions between core TOM subcomplexes; its IMS domain transfers preproteins to Tim50 of the TIM23 complex and is degraded by the Yme1 AAA protease via Mgr1/Mgr3 adapters; CK2 phosphorylates its precursor at Ser44/Ser46 to promote import, CK1 phosphorylates Thr57 to stimulate assembly with Tom20, and PKA phosphorylates Thr76 to impair import — with CK2-dependent phosphorylation of mammalian TOMM22 being a critical switch for mitophagy in skeletal muscle; porin (Por1) regulates Tom22 integration into the trimeric TOM complex and modulates TOM complex dynamics; Tom22 additionally functions as a mitochondrial receptor for pro-apoptotic Bax, facilitating its membrane insertion via conformational changes, and plays roles in steroidogenesis and mitochondrial fusion through interactions with 3βHSD2 and Mfn1, respectively."},"narrative":{"mechanistic_narrative":"TOMM22 (Tom22) is the central organizer and presequence receptor of the mitochondrial outer-membrane TOM translocase, coordinating recognition of incoming preproteins and the architecture of the import channel [PMID:10519552, PMID:9252394]. Its cytosolic domain selectively binds presequence-carrying preproteins in a salt-sensitive manner, engaging both the C-terminal part of the presequence and the N-terminal part of the mature protein, and it docks the peripheral receptors Tom20 and Tom70; loss of Tom22 dissociates the translocase into core complexes and abolishes tight channel gating [PMID:10519552, PMID:9252394, PMID:10347216, PMID:10982837]. Cryo-EM shows the cytosolic domain forms a three-helix bundle shared with Tom20, with helix H1 critical for presequence binding [PMID:35733257]. The single transmembrane domain stabilizes interactions among core TOM subcomplexes, while Tom40 and Tom22 together form a stable channel-active core (GIP) unit [PMID:10519552, PMID:11259583]. Tom22 acts along the same recognition pathway as Tom20 and then hands substrates across the membrane: its intermembrane-space (IMS) domain serves as a trans binding site that transfers preproteins to Tim50 of the TIM23 complex [PMID:9343421, PMID:18063580, PMID:21896724]. Import efficiency is tuned by phosphorylation — CK2 phosphorylates the precursor at Ser44/Ser46 to promote import, CK1 phosphorylates Thr57 to stimulate assembly with Tom20, and PKA phosphorylates Thr76 to impair import — and in mammalian skeletal muscle CK2 (CSNK2)-dependent phosphorylation of TOMM22 governs its precursor-binding affinity and thereby PINK1-driven mitophagy [PMID:24093680, PMID:29165030]. Tom22 levels are controlled by turnover through the inner-membrane Yme1 AAA protease via Mgr1/Mgr3 adaptors that recognize its IMS domain, and by the porin Por1, which sequesters Tom22 to modulate trimeric versus dimeric TOM assembly [PMID:30738703, PMID:29138251]. Beyond canonical import, Tom22 functions as a mitochondrial receptor for pro-apoptotic Bax, recognizing the GALLL motif in Bax helix α1 and triggering conformational changes that drive Bax membrane insertion and pore formation [PMID:17096026, PMID:39043635], and it participates in steroidogenesis through a complex with 3βHSD2 [PMID:26787839].","teleology":[{"year":1997,"claim":"Established that Tom22 is a bona fide presequence receptor distinct from Tom20 and Tom70, defining its molecular role in substrate recognition.","evidence":"In vitro binding of purified cytosolic receptor domains to mitochondrial preproteins with presequence-peptide competition","pmids":["9252394"],"confidence":"High","gaps":["Did not resolve which presequence residues are bound","Did not address membrane-embedded receptor behavior"]},{"year":1997,"claim":"Showed that the IMS domain of Tom22 provides a trans binding site for incoming preproteins, extending its receptor role across the outer membrane.","evidence":"Import assays with yeast mitochondria lacking the Tom22 IMS domain and two-step import protocols","pmids":["9343421"],"confidence":"High","gaps":["Did not identify the downstream acceptor of the IMS domain","Essentiality only manifest when cytosolic domains removed"]},{"year":1999,"claim":"Defined Tom22 as the structural organizer of the TOM complex, linking its transmembrane domain to complex integrity and channel gating and its cytosolic domain to Tom20/Tom70 docking.","evidence":"Genetic deletion in yeast with biochemical assembly and channel-gating analysis","pmids":["10519552"],"confidence":"High","gaps":["No structural basis for gating control","Did not map the docking interfaces with Tom20/Tom70"]},{"year":1999,"claim":"Mapped the cytosolic-domain binding site to the C-terminal presequence and N-terminal mature segments, distinguishing presequence from non-cleavable carrier substrates.","evidence":"Peptide-scan binding of purified cytosolic domain to CoxIV and phosphate carrier-derived peptides","pmids":["10347216"],"confidence":"High","gaps":["Peptide-array binding may not reflect folded-substrate geometry","Did not test recognition in intact complex"]},{"year":2000,"claim":"Demonstrated functional conservation by showing human TOM22 complements yeast Δtom22 and retains domain-specific receptor and Tom20-interaction functions.","evidence":"Immunoprecipitation, deletion-mutant import assays, and yeast complementation","pmids":["10982837","10900208"],"confidence":"High","gaps":["Mammalian-specific regulation not addressed","No structure of human domains at this stage"]},{"year":2001,"claim":"Resolved the Tom40-Tom22 GIP core as a stable, channel-active unit that retains preproteins, clarifying the architecture beneath receptor function.","evidence":"Blue native PAGE, denaturant resistance assays, and electrophysiology of purified GIP complex","pmids":["11259583"],"confidence":"High","gaps":["Did not define Tom22 conformational contribution to gating","Retention mechanism not molecularly resolved"]},{"year":2007,"claim":"Placed Tom20 and Tom22 on the same targeting-signal recognition pathway, ordering the receptor handoff step.","evidence":"In organello TEV cleavage of receptor domains with import of diverse substrates","pmids":["18063580"],"confidence":"High","gaps":["Sequential versus simultaneous action not fully distinguished","Substrate-specific differences not exhaustively mapped"]},{"year":2011,"claim":"Resolved the substrate trajectory at residue resolution, showing the cytosolic domain accepts precursors and the IMS domain transfers them to Tim50/TIM23.","evidence":"In vivo and in organello site-specific photocrosslinking with substrate/presequence perturbation","pmids":["21896724"],"confidence":"High","gaps":["Kinetics of the handoff unresolved","Conformational coupling between domains not defined"]},{"year":2013,"claim":"Revealed that import and assembly of Tom22 itself are regulated by opposing kinases (CK2, CK1, PKA), connecting metabolic signaling to TOM biogenesis.","evidence":"In vitro kinase assays, MS site mapping, and import assays with phosphomimetic mutants in yeast","pmids":["24093680"],"confidence":"High","gaps":["Phosphatases reversing these marks not identified","In vivo dynamics of switching not quantified"]},{"year":2017,"claim":"Identified the turnover route for Tom22 via the Yme1 AAA protease using Mgr1/Mgr3 to recognize its IMS domain, establishing regulated degradation of the receptor.","evidence":"Immunoprecipitation and site-specific photocrosslinking with ATPase-mutant Yme1","pmids":["29138251"],"confidence":"High","gaps":["Physiological triggers of Tom22 degradation unclear","Dislocation mechanism of cytosolic domain not fully resolved"]},{"year":2019,"claim":"Showed Por1 sequesters Tom22 to tune trimeric versus dimeric TOM assembly and cell-cycle-dependent import preferences, adding a dynamic regulatory layer.","evidence":"Reciprocal Co-IP, BN-PAGE, and cell-cycle synchronization in yeast","pmids":["30738703"],"confidence":"High","gaps":["Mechanism of cell-cycle coupling not defined","Mammalian conservation untested here"]},{"year":2022,"claim":"Provided the structural basis of Tom22 function, showing a Tom20-like three-helix bundle with helix H1 driving presequence binding.","evidence":"Cryo-EM of human TOM core and TOM-Tom22/Tom20 complexes with structure-guided mutagenesis","pmids":["35733257"],"confidence":"High","gaps":["Dynamic substrate-bound states not captured","Full receptor handoff geometry to TIM23 not resolved"]},{"year":2018,"claim":"Connected CK2 phosphorylation of mammalian TOMM22 to mitophagy control in skeletal muscle, linking the regulatory switch to PINK1-driven quality control.","evidence":"Muscle-specific Csnk2b KO mouse, in vitro phosphorylation, phosphomimetic rescue, and OCR measurements","pmids":["29165030"],"confidence":"High","gaps":["Mechanism linking precursor-binding affinity to PINK1 accumulation not fully resolved","Tissue specificity of the switch unexplored"]},{"year":2024,"claim":"Reconstituted Tom22's pro-apoptotic receptor function, showing it recognizes the Bax GALLL motif and drives Bax conformational change, insertion, and pore formation.","evidence":"Cell-free nanodisc synthesis, liposome permeabilization, and Bax mutagenesis","pmids":["17096026","39043635","22198199"],"confidence":"Medium","gaps":["In vivo relevance to apoptotic threshold not established","Relationship to canonical import function unclear"]},{"year":2024,"claim":"Extended Tom22 function to disease-relevant import capacity, showing TOMM22 levels set mitochondrial respiratory protein import and are stabilized against ubiquitin-dependent degradation by partner proteins.","evidence":"TOMM22 KD/OE with import and Seahorse assays in cancer cells; Co-IP and ubiquitination/rescue assays with BTN3A3","pmids":["37878010","42069175"],"confidence":"Medium","gaps":["E3 ligase mediating TOMM22 ubiquitination not identified","Direct versus indirect respiratory effects not separated"]},{"year":null,"claim":"How Tom22's multiple non-import roles (Bax activation, steroidogenesis, mitochondrial fusion, Aβ reception) are integrated with, or partitioned from, its core translocase function within a single receptor remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model spanning import and apoptotic functions","Physiological conditions selecting each role undefined","Mammalian regulation of moonlighting functions largely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,7,9,11]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,1,5,20]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,7]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[17]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[10,21,26,29]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,3,7]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,7,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,24]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[13,26]}],"complexes":["TOM complex","TOM core / GIP complex (Tom40-Tom22)"],"partners":["TOMM40","TOMM20","TOMM70","TIM50","BAX","YME1","POR1","MFN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NS69","full_name":"Mitochondrial import receptor subunit TOM22 homolog","aliases":["1C9-2","Translocase of outer membrane 22 kDa subunit homolog"],"length_aa":142,"mass_kda":15.5,"function":"Central receptor 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). Together with the peripheral receptor TOMM20, functions as the transit peptide receptor and facilitates the movement of preproteins into the translocation pore (PubMed:10982837). 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). Required for the translocation across the mitochondrial outer membrane of cytochrome P450 monooxygenases (By similarity)","subcellular_location":"Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/Q9NS69/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TOMM22","classification":"Common Essential","n_dependent_lines":1198,"n_total_lines":1208,"dependency_fraction":0.9917218543046358},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TOMM20A","stoichiometry":10.0},{"gene":"CYB5R3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TOMM22","total_profiled":1310},"omim":[{"mim_id":"620258","title":"TRANSMEMBRANE PROTEIN 160; TMEM160","url":"https://www.omim.org/entry/620258"},{"mim_id":"607980","title":"TRANSLOCASE OF OUTER MITOCHONDRIAL MEMBRANE 7; TOMM7","url":"https://www.omim.org/entry/607980"},{"mim_id":"607046","title":"TRANSLOCASE OF OUTER MITOCHONDRIAL MEMBRANE 22; TOMM22","url":"https://www.omim.org/entry/607046"},{"mim_id":"118950","title":"CITRATE SYNTHASE; CS","url":"https://www.omim.org/entry/118950"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Mitochondria","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TOMM22"},"hgnc":{"alias_symbol":["TOM22"],"prev_symbol":[]},"alphafold":{"accession":"Q9NS69","domains":[{"cath_id":"1.20.5","chopping":"56-120","consensus_level":"medium","plddt":86.2826,"start":56,"end":120}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NS69","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NS69-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NS69-F1-predicted_aligned_error_v6.png","plddt_mean":71.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TOMM22","jax_strain_url":"https://www.jax.org/strain/search?query=TOMM22"},"sequence":{"accession":"Q9NS69","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NS69.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NS69/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NS69"}},"corpus_meta":[{"pmid":"10519552","id":"PMC_10519552","title":"Tom22 is a multifunctional organizer 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In the absence of Tom22, the translocase dissociates into core complexes and loses tight channel gating control.\",\n      \"method\": \"Genetic deletion of Tom22 in yeast combined with biochemical analysis of TOM complex assembly and channel gating\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with multiple defined biochemical phenotypes (complex dissociation, channel gating defects, receptor docking), replicated across multiple experimental approaches\",\n      \"pmids\": [\"10519552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The purified cytosolic domain of Tom22 selectively recognizes presequence-carrying preproteins in a salt-sensitive manner, functioning as a presequence receptor distinct from Tom20 and Tom70.\",\n      \"method\": \"In vitro binding assays with purified recombinant cytosolic domains of Tom20, Tom22, and Tom70 against mitochondrial preproteins; competition with synthetic presequence peptides\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro reconstitution with purified proteins, multiple substrate tests, competition assays\",\n      \"pmids\": [\"9252394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Tom22 cytosolic domain binds to segments corresponding to the carboxyl-terminal part of the presequence and the amino-terminal part of the mature protein of presequence-carrying preproteins (CoxIV), but does not efficiently bind multiple segments of the non-cleavable phosphate carrier.\",\n      \"method\": \"Binding of purified cytosolic receptor domains to cellulose-bound peptide scans (13-mer peptide libraries) derived from CoxIV and phosphate carrier\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic in vitro peptide-scan binding with purified protein, multiple substrates tested\",\n      \"pmids\": [\"10347216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The intermembrane space (IMS) domain of Tom22 functions as a trans binding site for preproteins with N-terminal targeting sequences during outer membrane translocation, consistent with the acid chain hypothesis; this function becomes essential when cytosolic receptor domains are removed or during two-step import.\",\n      \"method\": \"Import assays using yeast mutant mitochondria lacking the IMS domain of Tom22; two-step import protocol (accumulation without ΔΨ then import after ΔΨ restoration); removal of cytosolic receptor domains\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic and biochemical approaches in yeast, consistent with replicated findings across labs\",\n      \"pmids\": [\"9343421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Tom40 and Tom22 form a highly stable core unit (GIP complex) that retains accumulated preproteins and exhibits characteristic TOM channel activity with two coupled conductance states; the GIP complex is resistant to urea and alkaline pH, and preprotein retention is not dependent on ionic interactions.\",\n      \"method\": \"Blue native PAGE, urea/salt/detergent treatment of isolated TOM complexes, electrophysiology of purified GIP complex from outer membrane vesicles\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution of channel activity, multiple biochemical dissection methods, electrophysiology\",\n      \"pmids\": [\"11259583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TOM22 functions as a mitochondrial receptor for the pro-apoptotic protein Bax; the interaction involves the first alpha helix of Bax and two central alpha helices. Knockdown of TOM22 inhibits Bax association with mitochondria and prevents Bax-dependent apoptosis.\",\n      \"method\": \"Bacterial two-hybrid assay, crosslinking strategies, peptide mapping, antisense knockdown of TOM22, yeast haploid strain with reduced TOM22\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (two-hybrid, crosslinking, peptide mapping, KD with functional readout), consistent findings\",\n      \"pmids\": [\"17096026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Tom20 and Tom22 are involved in the same step or sequential steps along the same pathway for targeting signal recognition during mitochondrial protein import; deletion of their receptor domains has similar effects across diverse import substrates.\",\n      \"method\": \"In vitro cleavage of receptor domains via introduced TEV protease sites in yeast; import assays of multiple mitochondrial precursor proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic in organello domain-deletion approach with multiple substrates across different import pathways\",\n      \"pmids\": [\"18063580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The cytosolic receptor domain of Tom22 accepts substrate precursor proteins, and the IMS domain of Tom22 transfers them to Tim50 of the inner-membrane translocator TIM23 complex, as mapped at single amino acid residue resolution in vivo.\",\n      \"method\": \"In vivo and in organello site-specific photocrosslinking; changes in crosslinking patterns induced by excess substrate or presequence peptides\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific photocrosslinking at residue-level resolution both in vivo and in organello, functional perturbation controls\",\n      \"pmids\": [\"21896724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CK2 constitutively phosphorylates the cytosolic precursor of Tom22 at Ser44 and Ser46, promoting its import into the TOM complex. CK1 (bound to mitochondria) phosphorylates Tom22 at Thr57 and stimulates assembly of Tom22 and Tom20. PKA phosphorylates the precursor of Tom22 at Thr76 and impairs its import, acting oppositely to CK1 and CK2.\",\n      \"method\": \"In vitro kinase assays, phosphorylation site mapping by mass spectrometry, import assays with phosphomimetic/phospho-null mutants, glucose-stimulated signaling experiments in yeast\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro kinase assays with site mapping, multiple kinases tested, import functional readout, multiple orthogonal methods\",\n      \"pmids\": [\"24093680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human TOM22 (hTom22) forms a complex with Tom20, functions as an import receptor via its cytosolic domain, and complements Δtom22 yeast cells; the C-terminal segment of the cytosolic domain is important for presequence binding, the N-terminal domain binds the mature portion of preproteins, and an internal segment of the cytosolic domain mediates interaction with Tom20.\",\n      \"method\": \"Immunoprecipitation, import inhibition assay with deletion mutants, cell-free binding studies, complementation of yeast Δtom22\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple domain-mapping experiments with defined deletion mutants, complementation assay, binding studies\",\n      \"pmids\": [\"10982837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Mammalian TOM22 (1C9-2) is stably associated with TOM40 in an ~400 kDa complex at the mitochondrial outer membrane and functionally complements Δtom22 yeast cells for growth and mitochondrial protein import.\",\n      \"method\": \"Immunopurification, blue native PAGE, import inhibition with antibodies, complementation of yeast Δtom22\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical complex identification, import inhibition, yeast complementation — multiple orthogonal methods\",\n      \"pmids\": [\"10900208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structure of human TOM core complex at 2.53 Å, and TOM complex with Tom22 and Tom20 cytosolic domains at 3.74 Å, reveals that Tom20 and Tom22 share a similar three-helix bundle structural feature in their cytosolic domains. Structure-guided mutagenesis shows the Tom22 cytosolic domain is responsible for presequence binding, with helix H1 being critical.\",\n      \"method\": \"Cryo-EM structure determination, structure-guided mutagenesis, biochemical binding assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure combined with mutagenesis and biochemical validation\",\n      \"pmids\": [\"35733257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In mammalian skeletal muscle, CSNK2/CK2-mediated phosphorylation of TOMM22 controls mitophagy: loss of CSNK2 reduces TOMM22 phosphorylation and its binding affinity for mitochondrial precursor proteins, leading to PINK1 accumulation and mitophagy. Phosphomimetic TOMM22 rescues oxygen consumption rate and normalizes mitophagy in Csnk2b-KO muscle.\",\n      \"method\": \"Skeletal muscle-specific Csnk2b conditional knockout mouse, in vitro phosphorylation assays with muscle lysates, electron microscopy for autophagosomes, electroporation of phosphomimetic Tomm22 in vivo, oxygen consumption rate measurement\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic KO model plus in vitro phosphorylation assay, functional rescue with phosphomimetic, multiple phenotypic readouts\",\n      \"pmids\": [\"29165030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Porin (Por1) acts as a sink to bind newly imported Tom22, modulating its integration into the trimeric TOM complex. Por1 sequestration of Tom22 dissociated from the trimeric TOM complex enhances the dimeric TOM complex (lacking Tom22), which is preferable for import of TIM40/MIA-dependent proteins. Por1 also contributes to cell-cycle-dependent variation of the functional trimeric TOM complex.\",\n      \"method\": \"Co-immunoprecipitation, blue native PAGE, genetic analysis, cell-cycle synchronization experiments in yeast\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, BN-PAGE complex analysis, genetic manipulation, multiple functional readouts in yeast\",\n      \"pmids\": [\"30738703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"A short segment of the cytosolic domain of Neurospora TOM22 contains a novel internal import signal with a net positive charge that is essential for targeting and assembly of TOM22 into the outer membrane; the transmembrane segment and IMS domain alone are insufficient for import.\",\n      \"method\": \"In vitro import studies with TOM22 deletion and charge-reversal mutants in Neurospora\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis with in vitro import readout, single lab\",\n      \"pmids\": [\"9565567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"An abundance of negative charges in the cytosolic domain of Neurospora TOM22 is not essential for preprotein binding or import; however, other structural features of this domain are required (deletion of the entire region abolishes function).\",\n      \"method\": \"Systematic charge-neutralization mutagenesis of the cytosolic domain, mitochondrial import assays, precursor binding assays with outer membrane vesicles, complementation in heterokaryon\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis with multiple functional readouts, but single lab, result is primarily negative (charges not essential)\",\n      \"pmids\": [\"9584158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Rat TOM22 targeting to the mitochondrial outer membrane and assembly into the TOM complex requires three structural elements: an acidic alpha-helical cytoplasmic import sequence ~30 residues upstream of the TMD, the TMD with appropriate hydrophobicity, and a 20-residue C-terminal IMS segment. The import sequence interacts intramolecularly with TMD and C-tail, and also with Tom20 by yeast two-hybrid.\",\n      \"method\": \"Systematic deletion/mutation analysis in HeLa cells with confocal microscopy, cell fractionation, blue native PAGE, yeast two-hybrid\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis in mammalian cells with multiple readouts, two-hybrid for interaction, single lab\",\n      \"pmids\": [\"14985332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The cytosolic domain of Tom22 has chaperone-like activity, preventing substrate proteins (e.g., citrate synthase) from aggregating. This activity is inhibited by presequence peptide, suggesting the presequence binding site and the chaperone active site are identical or overlapping.\",\n      \"method\": \"In vitro aggregation suppression assays with purified cytosolic domains of Tom20 and Tom22; competition with presequence peptide\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro biochemical assay with purified proteins, but single lab and single substrate tested\",\n      \"pmids\": [\"14699115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NMR studies of plant ScTom22 show it binds presequences; AtTom22 (plant) does not bind presequences but instead binds to the AtTom20 receptor at the same site as presequences, suggesting it competes with presequences to enable their progression along the import pathway.\",\n      \"method\": \"NMR spectroscopy of cytosolic domains of AtTom20, AtTom22, and ScTom22 with presequence peptides\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural/interaction data, but single lab, involves plant orthologs\",\n      \"pmids\": [\"21087612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mitochondrial inner-membrane AAA protease Yme1 degrades outer-membrane Tom22 via its adaptor proteins Mgr1 and Mgr3, which recognize the IMS domain of Tom22; the ATPase activity of Yme1 can dislocate the cytoplasmic domain of substrates into the IMS for proteolysis.\",\n      \"method\": \"Immunoprecipitation, in vivo site-specific photocrosslinking to map Mgr1/Mgr3 interactions with Tom22 IMS domain, ATPase-mutant Yme1 analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal immunoprecipitation plus site-specific photocrosslinking with mechanistic mutants, two orthogonal methods\",\n      \"pmids\": [\"29138251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TOMM22 is the main mitochondrial receptor for amyloid-β (Aβ) peptides in yeast mitochondria; residues 25-42 of Aβ mediate the specific interaction with TOMM22. Aβ is then proposed to be transferred to TOMM40 and transported through the TOM channel.\",\n      \"method\": \"Yeast genetics (tom22 deletion), direct binding assays with Aβ peptide fragments, mitochondrial import assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and biochemical evidence in yeast, but single lab and some mechanistic steps remain proposed\",\n      \"pmids\": [\"29925587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tom22 is essential for steroidogenesis: Tom22 knockdown abolishes progesterone conversion in steroidogenic cells, and Tom22 forms a ~500 kDa complex with 3βHSD2 at the mitochondrial outer membrane. The IMS C-terminal segment of Tom22 interacts with a specific region of 3βHSD2. Tom22 absence inhibits 3βHSD2 expression but not import of CYP450scc or aldosterone synthase.\",\n      \"method\": \"siRNA knockdown, blue native PAGE, electron microscopy for localization, co-immunoprecipitation, steroidogenesis functional assays in MA-10 and NCI cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, BN-PAGE, EM localization, siRNA with functional readout, single lab\",\n      \"pmids\": [\"26787839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tom22, aldosterone synthase (P450c11AS), and intramitochondrial 30-kDa StAR form a 110-kDa trimolecular complex required for aldosterone synthesis in the rat heart, as demonstrated by protein crosslinking and co-immunoprecipitation.\",\n      \"method\": \"Blue native PAGE, immunoblotting, protein crosslinking, co-immunoprecipitation, mass spectrometry\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods (crosslinking, Co-IP, BN-PAGE, MS) in single lab\",\n      \"pmids\": [\"33526603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human Tom22 cytosolic domain expression in yeast increases Bax mitochondrial localization but decreases the proportion of active Bax and interferes with Bax oligomerization, suggesting the cytosolic domain of Tom22 promotes a membrane-competent but non-oligomeric Bax conformation.\",\n      \"method\": \"Co-immunoprecipitation, blue native PAGE, yeast expression system with human Bax\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and BN-PAGE in yeast expression system, single lab, two methods\",\n      \"pmids\": [\"22198199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tom22 stimulates Bax membrane insertion in a cell-free nanodisc system: Tom22 recognizes the GALLL hydrophobic motif in Bax helix α1, triggering conformational changes that lead to extrusion and membrane insertion of the C-terminal hydrophobic Hα9. Tom22-activated Bax forms ~5-nm pores in nanodiscs. D154Y and T174P mutations in Bax impair this Tom22-dependent mechanism.\",\n      \"method\": \"Cell-free synthesis with nanodiscs, liposome permeabilization assay, mutagenesis of Bax\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with nanodiscs and mutagenesis, but single lab\",\n      \"pmids\": [\"39043635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Molecular dynamics simulations reveal that Tom22 helices undergo large motions coupled to global structural rearrangements in the TOM complex, particularly with the α2 helix within the Tom40 pore, and restraining Tom22 helices reduces ion permeability, linking Tom22 receptor dynamics to pore gating.\",\n      \"method\": \"All-atom molecular dynamics simulations (microsecond-scale) with and without restraints on Tom22 helices; ion permeability measurements in silico\",\n      \"journal\": \"Journal of chemical information and modeling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational simulation only, no direct experimental validation in this paper\",\n      \"pmids\": [\"41172152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tom22 interacts with Mfn1 and modulates mitochondrial fusion: Tom22 deletion reduces mitochondrial fusion, ATP production, and increases apoptosis in endothelial cells; Tom22 overexpression restores mitochondrial dynamics and OXPHOS impaired by high glucose.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression in HUVECs, mitochondrial morphology imaging, ATP measurement\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for interaction, KD and OE with functional readouts, single lab\",\n      \"pmids\": [\"31236191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mitochondrial BKCa channel interacts with Tom22 via its transmembrane domain, and the BKCa 50-amino-acid DEC splice insert facilitates interaction with ANT but not Tom22. BKCa and Tom22 co-immunoprecipitate and co-segregate into mitochondrial fractions.\",\n      \"method\": \"Directed proteomics, co-immunoprecipitation, cell fractionation in HEK293T cells\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"27592226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Certain cytochrome P450 proteins with chimeric mitochondrial targeting signals (CYP+33/1A1, CYP2B1) can bypass TOM20, TOM22, and TOM70 for translocation through TOM40, while others (CYP+5/1A1, CYP2E1) bypass TOM20 and TOM22 but require TOM70. This bypass occurs when CYP proteins interact sequentially with both Hsp70 and Hsp90.\",\n      \"method\": \"Antibody inhibition of specific TOM subunits, import assays, co-immunoprecipitation with chaperones\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple import pathway experiments with antibody inhibition and chaperone co-IP, single lab\",\n      \"pmids\": [\"19401463\", \"18480056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TOMM22 overexpression in pancreatic cancer cells increases import of mitochondrial proteins associated with respiration, RCI activity, NAD+/NADH ratio, oxygen consumption rate, membrane potential, and ATP production. TOMM22 silencing decreases these and suppresses malignant growth, placing TOMM22 upstream of mitochondrial respiratory function.\",\n      \"method\": \"TOMM22 siRNA knockdown and overexpression in pancreatic cancer cell lines, mitochondrial protein import assays, RCI activity measurement, Seahorse metabolic analysis\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and OE with multiple functional readouts including import assays, single lab\",\n      \"pmids\": [\"37878010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"BTN3A3 interacts with TOMM22 at mitochondria (identified by mass spectrometry and Co-IP); sorafenib stress promotes BTN3A3 mitochondrial translocation where it shields TOMM22 from ubiquitin-proteasome-dependent degradation. BTN3A3 deficiency leads to TOMM22 depletion, mitochondrial fragmentation, and impaired OXPHOS.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, ubiquitination assays, TOMM22 knockdown/rescue, live-cell imaging of BTN3A3 translocation, in vivo xenograft\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP, ubiquitination assay, rescue experiments, single lab\",\n      \"pmids\": [\"42069175\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TOMM22 (Tom22) is the central receptor and organizer of the mitochondrial outer membrane TOM complex: its cytosolic domain binds presequence-carrying preproteins (via a three-helix bundle, with helix H1 critical) and docks peripheral receptors Tom20 and Tom70; its single transmembrane domain stabilizes interactions between core TOM subcomplexes; its IMS domain transfers preproteins to Tim50 of the TIM23 complex and is degraded by the Yme1 AAA protease via Mgr1/Mgr3 adapters; CK2 phosphorylates its precursor at Ser44/Ser46 to promote import, CK1 phosphorylates Thr57 to stimulate assembly with Tom20, and PKA phosphorylates Thr76 to impair import — with CK2-dependent phosphorylation of mammalian TOMM22 being a critical switch for mitophagy in skeletal muscle; porin (Por1) regulates Tom22 integration into the trimeric TOM complex and modulates TOM complex dynamics; Tom22 additionally functions as a mitochondrial receptor for pro-apoptotic Bax, facilitating its membrane insertion via conformational changes, and plays roles in steroidogenesis and mitochondrial fusion through interactions with 3βHSD2 and Mfn1, respectively.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TOMM22 (Tom22) is the central organizer and presequence receptor of the mitochondrial outer-membrane TOM translocase, coordinating recognition of incoming preproteins and the architecture of the import channel [#0, #1]. Its cytosolic domain selectively binds presequence-carrying preproteins in a salt-sensitive manner, engaging both the C-terminal part of the presequence and the N-terminal part of the mature protein, and it docks the peripheral receptors Tom20 and Tom70; loss of Tom22 dissociates the translocase into core complexes and abolishes tight channel gating [#0, #1, #2, #9]. Cryo-EM shows the cytosolic domain forms a three-helix bundle shared with Tom20, with helix H1 critical for presequence binding [#11]. The single transmembrane domain stabilizes interactions among core TOM subcomplexes, while Tom40 and Tom22 together form a stable channel-active core (GIP) unit [#0, #4]. Tom22 acts along the same recognition pathway as Tom20 and then hands substrates across the membrane: its intermembrane-space (IMS) domain serves as a trans binding site that transfers preproteins to Tim50 of the TIM23 complex [#3, #6, #7]. Import efficiency is tuned by phosphorylation — CK2 phosphorylates the precursor at Ser44/Ser46 to promote import, CK1 phosphorylates Thr57 to stimulate assembly with Tom20, and PKA phosphorylates Thr76 to impair import — and in mammalian skeletal muscle CK2 (CSNK2)-dependent phosphorylation of TOMM22 governs its precursor-binding affinity and thereby PINK1-driven mitophagy [#8, #12]. Tom22 levels are controlled by turnover through the inner-membrane Yme1 AAA protease via Mgr1/Mgr3 adaptors that recognize its IMS domain, and by the porin Por1, which sequesters Tom22 to modulate trimeric versus dimeric TOM assembly [#13, #19]. Beyond canonical import, Tom22 functions as a mitochondrial receptor for pro-apoptotic Bax, recognizing the GALLL motif in Bax helix \\u03b11 and triggering conformational changes that drive Bax membrane insertion and pore formation [#5, #24], and it participates in steroidogenesis through a complex with 3\\u03b2HSD2 [#21].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that Tom22 is a bona fide presequence receptor distinct from Tom20 and Tom70, defining its molecular role in substrate recognition.\",\n      \"evidence\": \"In vitro binding of purified cytosolic receptor domains to mitochondrial preproteins with presequence-peptide competition\",\n      \"pmids\": [\"9252394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which presequence residues are bound\", \"Did not address membrane-embedded receptor behavior\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed that the IMS domain of Tom22 provides a trans binding site for incoming preproteins, extending its receptor role across the outer membrane.\",\n      \"evidence\": \"Import assays with yeast mitochondria lacking the Tom22 IMS domain and two-step import protocols\",\n      \"pmids\": [\"9343421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the downstream acceptor of the IMS domain\", \"Essentiality only manifest when cytosolic domains removed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined Tom22 as the structural organizer of the TOM complex, linking its transmembrane domain to complex integrity and channel gating and its cytosolic domain to Tom20/Tom70 docking.\",\n      \"evidence\": \"Genetic deletion in yeast with biochemical assembly and channel-gating analysis\",\n      \"pmids\": [\"10519552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural basis for gating control\", \"Did not map the docking interfaces with Tom20/Tom70\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Mapped the cytosolic-domain binding site to the C-terminal presequence and N-terminal mature segments, distinguishing presequence from non-cleavable carrier substrates.\",\n      \"evidence\": \"Peptide-scan binding of purified cytosolic domain to CoxIV and phosphate carrier-derived peptides\",\n      \"pmids\": [\"10347216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Peptide-array binding may not reflect folded-substrate geometry\", \"Did not test recognition in intact complex\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated functional conservation by showing human TOM22 complements yeast \\u0394tom22 and retains domain-specific receptor and Tom20-interaction functions.\",\n      \"evidence\": \"Immunoprecipitation, deletion-mutant import assays, and yeast complementation\",\n      \"pmids\": [\"10982837\", \"10900208\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian-specific regulation not addressed\", \"No structure of human domains at this stage\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolved the Tom40-Tom22 GIP core as a stable, channel-active unit that retains preproteins, clarifying the architecture beneath receptor function.\",\n      \"evidence\": \"Blue native PAGE, denaturant resistance assays, and electrophysiology of purified GIP complex\",\n      \"pmids\": [\"11259583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define Tom22 conformational contribution to gating\", \"Retention mechanism not molecularly resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Placed Tom20 and Tom22 on the same targeting-signal recognition pathway, ordering the receptor handoff step.\",\n      \"evidence\": \"In organello TEV cleavage of receptor domains with import of diverse substrates\",\n      \"pmids\": [\"18063580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sequential versus simultaneous action not fully distinguished\", \"Substrate-specific differences not exhaustively mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the substrate trajectory at residue resolution, showing the cytosolic domain accepts precursors and the IMS domain transfers them to Tim50/TIM23.\",\n      \"evidence\": \"In vivo and in organello site-specific photocrosslinking with substrate/presequence perturbation\",\n      \"pmids\": [\"21896724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetics of the handoff unresolved\", \"Conformational coupling between domains not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed that import and assembly of Tom22 itself are regulated by opposing kinases (CK2, CK1, PKA), connecting metabolic signaling to TOM biogenesis.\",\n      \"evidence\": \"In vitro kinase assays, MS site mapping, and import assays with phosphomimetic mutants in yeast\",\n      \"pmids\": [\"24093680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatases reversing these marks not identified\", \"In vivo dynamics of switching not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified the turnover route for Tom22 via the Yme1 AAA protease using Mgr1/Mgr3 to recognize its IMS domain, establishing regulated degradation of the receptor.\",\n      \"evidence\": \"Immunoprecipitation and site-specific photocrosslinking with ATPase-mutant Yme1\",\n      \"pmids\": [\"29138251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological triggers of Tom22 degradation unclear\", \"Dislocation mechanism of cytosolic domain not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed Por1 sequesters Tom22 to tune trimeric versus dimeric TOM assembly and cell-cycle-dependent import preferences, adding a dynamic regulatory layer.\",\n      \"evidence\": \"Reciprocal Co-IP, BN-PAGE, and cell-cycle synchronization in yeast\",\n      \"pmids\": [\"30738703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of cell-cycle coupling not defined\", \"Mammalian conservation untested here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided the structural basis of Tom22 function, showing a Tom20-like three-helix bundle with helix H1 driving presequence binding.\",\n      \"evidence\": \"Cryo-EM of human TOM core and TOM-Tom22/Tom20 complexes with structure-guided mutagenesis\",\n      \"pmids\": [\"35733257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamic substrate-bound states not captured\", \"Full receptor handoff geometry to TIM23 not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected CK2 phosphorylation of mammalian TOMM22 to mitophagy control in skeletal muscle, linking the regulatory switch to PINK1-driven quality control.\",\n      \"evidence\": \"Muscle-specific Csnk2b KO mouse, in vitro phosphorylation, phosphomimetic rescue, and OCR measurements\",\n      \"pmids\": [\"29165030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking precursor-binding affinity to PINK1 accumulation not fully resolved\", \"Tissue specificity of the switch unexplored\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reconstituted Tom22's pro-apoptotic receptor function, showing it recognizes the Bax GALLL motif and drives Bax conformational change, insertion, and pore formation.\",\n      \"evidence\": \"Cell-free nanodisc synthesis, liposome permeabilization, and Bax mutagenesis\",\n      \"pmids\": [\"17096026\", \"39043635\", \"22198199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance to apoptotic threshold not established\", \"Relationship to canonical import function unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended Tom22 function to disease-relevant import capacity, showing TOMM22 levels set mitochondrial respiratory protein import and are stabilized against ubiquitin-dependent degradation by partner proteins.\",\n      \"evidence\": \"TOMM22 KD/OE with import and Seahorse assays in cancer cells; Co-IP and ubiquitination/rescue assays with BTN3A3\",\n      \"pmids\": [\"37878010\", \"42069175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating TOMM22 ubiquitination not identified\", \"Direct versus indirect respiratory effects not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Tom22's multiple non-import roles (Bax activation, steroidogenesis, mitochondrial fusion, A\\u03b2 reception) are integrated with, or partitioned from, its core translocase function within a single receptor remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model spanning import and apoptotic functions\", \"Physiological conditions selecting each role undefined\", \"Mammalian regulation of moonlighting functions largely uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 7, 9, 11]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1, 5, 20]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 7]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005741\", \"supporting_discovery_ids\": [0, 4, 10, 11]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [10, 21, 26, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 3, 7]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 7, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 24]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [13, 26]}\n    ],\n    \"complexes\": [\n      \"TOM complex\",\n      \"TOM core / GIP complex (Tom40-Tom22)\"\n    ],\n    \"partners\": [\n      \"TOMM40\",\n      \"TOMM20\",\n      \"TOMM70\",\n      \"TIM50\",\n      \"BAX\",\n      \"YME1\",\n      \"POR1\",\n      \"MFN1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}