Affinage

TOMM40

Mitochondrial import receptor subunit TOM40 homolog · UniProt O96008

Length
361 aa
Mass
37.9 kDa
Annotated
2026-04-28
100 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TOMM40 encodes the central pore-forming β-barrel subunit of the translocase of the outer mitochondrial membrane (TOM complex), serving as the principal protein-conducting channel for nearly all nuclear-encoded mitochondrial preproteins. Reconstituted Tom40 forms a cation-selective, high-conductance channel (~22 Å diameter) with dominant β-sheet structure that specifically recognizes mitochondrial targeting presequences on both cis and trans sides of the pore, actively sorting precursors to distinct downstream import pathways rather than functioning as a passive conduit (PMID:9774109, PMID:12743032, PMID:25002531). Tom40 biogenesis proceeds through sequential intermediates involving Hsp90-dependent cytosolic delivery, TOM complex surface binding, SAM/TOB complex-mediated β-barrel insertion regulated by Tom5, Tom7, and Mdm10, with PKA phosphorylation acting as a negative regulator of this process (PMID:10427088, PMID:15644312, PMID:22419819). Beyond its core import function, Tom40 serves as a platform at ER–mitochondria contact sites where it bridges BAP31 to promote complex I assembly via NDUFS4 import, recruits Atg2A/TOM70 for phagophore expansion during autophagy, facilitates StAR-dependent cholesterol transport into steroidogenic mitochondria, and is selectively degraded by the ubiquitin–proteasome system upon α-synuclein accumulation, linking its loss to mitochondrial dysfunction in neurodegeneration (PMID:31206022, PMID:31412244, PMID:37035007, PMID:39695091).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1997 High

    Established that Tom40 constitutes the trans presequence-binding site within the import pore, resolving how preproteins are handed off from surface receptors (Tom20/Tom22) to the translocation channel.

    Evidence Chemical cross-linking in isolated yeast mitochondria tracking presequence contacts during translocation

    PMID:9228044

    Open questions at the time
    • No structural resolution of binding interface
    • Cross-linking captures proximity but not direct binding stoichiometry
  2. 1998 High

    Demonstrated that Tom40 alone forms the protein-conducting channel of the TOM complex, establishing it as a β-barrel pore with cation selectivity and direct presequence recognition — the foundational mechanistic model for mitochondrial protein import.

    Evidence Reconstitution of purified Tom40 into planar lipid bilayers with electrophysiology and presequence peptide binding assays

    PMID:9774109

    Open questions at the time
    • Pore structure at atomic resolution unknown
    • Oligomeric state of functional channel not defined
  3. 1999 High

    Mapped the biogenesis pathway of Tom40 itself, showing it proceeds through sequential stages — surface binding via Tom20, partial membrane insertion, and assembly into pre-existing TOM complexes — with the N-terminal segment required for final assembly but not targeting.

    Evidence In vitro import of truncation mutants with carbonate extraction and protease protection in yeast mitochondria

    PMID:10427088

    Open questions at the time
    • Identity of the insertion machinery (later shown to be SAM) not yet established
    • N-terminal segment's assembly role mechanistically undefined
  4. 2000 High

    Confirmed that mammalian TOM40 (rat OM38) is an essential core component of a ~400 kDa complex with TOM20, TOM22, and small Tom proteins, extending the yeast model to vertebrates.

    Evidence Immunoprecipitation, blue native PAGE, and reconstituted outer membrane vesicle import assay with immunodepletion

    PMID:10980201

    Open questions at the time
    • Subunit stoichiometry not resolved
    • Mammalian-specific regulatory features not yet explored
  5. 2001 High

    Resolved the oligomeric architecture of the functional import pore: Tom40 and Tom22 form a highly stable core unit containing two simultaneously active Tom40 channel pores, establishing the dimeric pore model.

    Evidence Blue native PAGE under varying stringency, electrophysiology of purified outer membrane vesicles, and reconstituted preprotein accumulation assays

    PMID:11259583 PMID:11402060

    Open questions at the time
    • No high-resolution structure
    • Whether two pores function cooperatively or independently unclear
  6. 2003 High

    Revealed that Tom40 is not a passive pore but actively sorts precursors: a single point mutation (W243R) selectively abolished transfer to TIM23 without affecting TIM54 or outer membrane pathways, proving pathway-specific recognition within the channel.

    Evidence Genetic screen of tom40 mutant library with in vitro import assays using pathway-specific substrates

    PMID:12743032

    Open questions at the time
    • Structural basis of sorting determinants unknown
    • Whether sorting involves distinct binding sites or conformational changes undetermined
  7. 2003 High

    Demonstrated Tom40 has chaperone-like activity, binding unfolded polypeptides and suppressing their aggregation, explaining how precursors traverse the channel without misfolding.

    Evidence Site-specific photocrosslinking showing up to 90 residues simultaneously associated with Tom40; in vitro aggregation suppression assay

    PMID:14595396

    Open questions at the time
    • Whether chaperone activity is passive (steric confinement) or active (specific interactions) unclear
    • No structural model of precursor-channel contacts
  8. 2004 High

    Mapped the preprotein recognition and conducting domain to the C-terminal membrane-embedded segment of Tom40 (enriched to ~62% β-sheet), showing sequential ionic then salt-resistant non-ionic interactions with preproteins.

    Evidence Recombinant domain truncation, FTIR/CD, preprotein binding assays, and planar lipid bilayer electrophysiology of rat Tom40

    PMID:15347672

    Open questions at the time
    • Exact residues mediating ionic vs non-ionic contacts not identified
    • No crystal structure
  9. 2004 High

    Established that intermembrane space components (small Tim chaperones) are required for an early Tom40 assembly intermediate with the SAM complex, linking IMS chaperone function to β-barrel biogenesis.

    Evidence Mitochondrial swelling and small Tim mutant analysis with in vitro import and blue native PAGE

    PMID:14978039

    Open questions at the time
    • Direct physical interaction between small Tims and Tom40 precursor not shown
    • Mechanism of IMS-to-SAM handoff unknown
  10. 2005 High

    Showed human Tom40 biogenesis requires Hsp90 for cytosolic delivery and Sam50 for membrane insertion, but unlike yeast, human Tom40 does not form a stable SAM intermediate — revealing species-specific assembly differences.

    Evidence In vitro import with Hsp90 inhibitor and Sam50 depletion, blue native PAGE in human cells

    PMID:15644312

    Open questions at the time
    • Why human Tom40 lacks a stable SAM intermediate mechanistically unexplained
    • Whether other cytosolic chaperones substitute for Hsp90 untested
  11. 2010 High

    Defined the regulatory network controlling Tom40 release from the SAM/TOB complex: Mdm10 controls timing of release, Tom7 bridges Tom40 and Mdm10 via transmembrane contacts, and Tom5 promotes a two-stage SAM interaction, with Mim1's role largely indirect through Tom5 import.

    Evidence In vivo photocrosslinking, bidirectional genetic manipulation of Mdm10/Tom7/Tom5/Mim1, in vitro import, blue native PAGE

    PMID:20111053 PMID:20668160 PMID:21036907

    Open questions at the time
    • Structural basis of the two SAM stages unknown
    • Temporal regulation under physiological conditions not measured
  12. 2011 High

    Structural modeling and topology mapping identified a 19-strand β-barrel architecture with two conserved polar slides lining the pore interior, one unique to Tom40, potentially mediating presequence recognition and distinguishing Tom40 from VDAC.

    Evidence Limited proteolysis with mass spectrometry, comparative modeling from VDAC-1 template (Neurospora crassa); substituted cysteine accessibility mapping (SCAM) confirmed β-strands and C-terminal IMS localization

    PMID:21888892 PMID:24947507

    Open questions at the time
    • No experimental high-resolution structure at atomic level at this time
    • Functional role of polar slides not validated by mutagenesis
  13. 2012 High

    Revealed two distinct regulatory mechanisms: voltage-dependent presequence translocation kinetics through the Tom40 channel (providing biophysical evidence of active translocation), and PKA-mediated phosphorylation of the Tom40 precursor as a negative regulator of its own biogenesis.

    Evidence Single-channel electrophysiology with kinetic analysis; in vitro kinase assay with phosphomimetic mutants and import reconstitution

    PMID:22225796 PMID:22419819

    Open questions at the time
    • In vivo relevance of PKA regulation under physiological signaling conditions not shown
    • Whether voltage dependence operates in vivo at native membrane potentials unclear
  14. 2013 High

    Linked Tom40 loss to Parkinson's disease pathology: TOM40 protein is reduced in PD patient brains and α-synuclein transgenic mice, associated with mtDNA deletions and energy deficits; lentiviral Tom40 restoration rescued mitochondrial function in vivo.

    Evidence Laser-capture microdissection of PD brains, α-synuclein transgenic mouse analysis, lentiviral Tom40 overexpression with ATP/respiratory complex/mtDNA readouts

    PMID:23626796

    Open questions at the time
    • Mechanism of α-synuclein-mediated Tom40 reduction not defined (later addressed)
    • Whether Tom40 restoration is neuroprotective long-term unknown
  15. 2014 High

    Mapped presequence contact sites on both cis and trans faces of the Tom40 β-barrel by mass spectrometry, and demonstrated that Tom40 occupies at least four distinct conductive conformations with state-dependent substrate affinity, establishing a dynamic gating model.

    Evidence Photoaffinity labeling with modified presequence peptides and MS; electrophysiology of full-length and truncated recombinant Tom40

    PMID:25002531 PMID:26336107

    Open questions at the time
    • Structural transitions between conformational states not resolved
    • Relationship between conformational states and sorting specificity unknown
  16. 2014 High

    Demonstrated that Tom40 serves as the entry portal for the influenza A PB1-F2 virulence factor, which translocates through Tom40 into the IMS to collapse membrane potential and suppress innate immune signaling (RIG-I and NLRP3).

    Evidence Tom40 knockdown/blocking, mitochondrial fractionation, membrane potential measurements, innate immune reporter assays

    PMID:25140902

    Open questions at the time
    • Whether PB1-F2 uses the same presequence recognition mechanism as endogenous substrates unclear
    • Generalizability to other viral proteins using Tom40 not established
  17. 2019 High

    Extended Tom40's functional repertoire beyond protein import to ER–mitochondria contact site biology: BAP31 bridges the ER to Tom40 to promote NDUFS4 import and complex I assembly, while Atg2A/TOM70 is recruited to Tom40 at MAM sites for phagophore expansion during autophagy.

    Evidence Reciprocal Co-IP, BAP31 knockout with complex I activity and oxygen consumption readouts; proteomic identification of Atg2A–TOM40 interaction with domain mapping and autophagy flux assays

    PMID:31206022 PMID:31412244

    Open questions at the time
    • Structural basis of BAP31–Tom40 and Atg2A–Tom40 interactions unknown
    • Whether these contact site functions require Tom40 channel activity or only scaffolding unclear
  18. 2023 Medium

    Identified Tom40 as a mediator of mitochondrial cholesterol import in steroidogenic cells, interacting with StAR at the outer membrane to facilitate cholesterol transfer from MAM-associated lipid complexes.

    Evidence Co-IP, Tom40 knockout, cholesterol transport and steroidogenesis assays in rat testicular tissue and MA-10 Leydig cells

    PMID:37035007

    Open questions at the time
    • Whether cholesterol traverses the Tom40 channel lumen or is handed off laterally into the membrane unknown
    • Single-lab finding awaits independent replication
    • Mechanism of StAR–Tom40 recognition not defined
  19. 2024 High

    Resolved the mechanism of α-synuclein-induced Tom40 loss: mitochondria-targeted oligomeric α-synuclein selectively triggers TOM40 (but not TOM20) degradation via the ubiquitin–proteasome system, directly linking α-synuclein pathology to selective TOM40 depletion and mitochondrial dysfunction.

    Evidence Co-IP of α-synuclein with TOM40/TOM20, UPS inhibitor rescue, Seahorse respirometry, mtDNA sequencing, ectopic TOM40 overexpression rescue

    PMID:39695091

    Open questions at the time
    • E3 ubiquitin ligase responsible for Tom40 ubiquitination not identified
    • Selectivity mechanism for TOM40 over TOM20 degradation unknown
    • In vivo validation in animal PD models not yet reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • High-resolution structural determination of the human TOM complex with substrates bound remains a key gap; the structural basis of Tom40's conformational switching, active sorting determinants, and the molecular architecture of its ER–mitochondria contact site interactions are unresolved.
  • No high-resolution cryo-EM or crystal structure of human TOM40 in complex with substrates reported in this timeline
  • Conformational gating mechanism not structurally resolved
  • How Tom40 integrates import, contact site scaffolding, and lipid transport functions remains unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0005198 structural molecule activity 2 GO:0044183 protein folding chaperone 1
Localization
GO:0005739 mitochondrion 6 GO:0005886 plasma membrane 5
Pathway
R-HSA-9609507 Protein localization 7 R-HSA-1852241 Organelle biogenesis and maintenance 6 R-HSA-1430728 Metabolism 2 R-HSA-9612973 Autophagy 1
Partners
ATG2ABAP31SAMM50STARTOMM20TOMM22TOMM5TOMM7
Complex memberships
BAP31-TOM40 ER-mitochondria bridging complexSAM/TOB complex (assembly intermediate)TOM complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Tom40 is the pore-forming subunit of the mitochondrial general import pore, forming a cation-selective high-conductance channel (~22 Å wide) that specifically binds to and transports mitochondrial-targeting sequences; reconstituted Tom40 exhibits beta-sheet structure and channel activity. Functional reconstitution into planar lipid bilayers, electrophysiology, in vitro binding assays with presequence peptides Nature High 9774109
1997 Tom40 forms the major part of the trans presequence-binding site; chemical cross-linking showed the presequence initially contacts Tom20/Tom22 at the cis site, then shifts to firm association with Tom40 as the preprotein enters the translocation pore. Chemical cross-linking in isolated mitochondria The Journal of biological chemistry High 9228044
2001 Tom40 and Tom22 form the functional core unit of the general import pore (GIP) complex; the GIP complex is highly stable (resistant to urea and alkaline pH) and contains two coupled, simultaneously active channel pores corresponding to two Tom40 subunits. Blue native PAGE, detergent solubilization under varying stringency, electrophysiology of purified outer membrane vesicles, preprotein accumulation assays Molecular and cellular biology High 11259583
2001 Purified Tom40 from Neurospora crassa forms an oligomeric high-conductance channel (~2.5 nm pore diameter) with ~31% beta-sheet structure; presequence peptides interact specifically with reconstituted Tom40 and decrease ion flow in a voltage-dependent manner. Biochemical purification, circular dichroism, FTIR spectroscopy, planar lipid bilayer electrophysiology, electron microscopy The Journal of cell biology High 11402060
1999 Tom40 biogenesis proceeds through sequential steps: initial surface binding (stimulated by import receptor Tom20), partial membrane insertion, and final assembly into pre-existing TOM complexes; the N-terminal segment is required for assembly but not outer membrane targeting. In vitro import assays with truncation mutants, carbonate extraction, protease protection The Journal of cell biology High 10427088
2003 Tom40 plays an active role in protein sorting: the tom40-97 point mutation (W243R) selectively abolishes transfer of precursors to the TIM23 complex without affecting transfer to TIM54 or outer membrane insertion, demonstrating Tom40 is not a passive pore. tom40 mutant library screen, in vitro import assays with selective substrates The EMBO journal High 12743032
2003 Tom40 binds non-native (unfolded/loosely folded) proteins and suppresses their aggregation; site-specific photocrosslinking showed translocating precursor segments of up to 90 residues are associated with Tom40, and a denatured protein bound to the Tom40 channel blocked further protein import. Site-specific photocrosslinking, in vitro aggregation suppression assay, import competition assay Nature structural biology High 14595396
2004 The membrane-embedded C-terminal segment of rat TOM40 (after residue 165) constitutes the preprotein recognition and conducting domain with enriched beta-structure (~62–63%); it binds preprotein through sequential ionic then salt-resistant non-ionic interactions and exhibits presequence-sensitive cation-selective channel activity. Recombinant protein purification and refolding, FTIR/CD spectroscopy, preprotein binding assays, planar lipid bilayer electrophysiology, domain truncation The Journal of biological chemistry High 15347672
2004 Components of the mitochondrial intermembrane space, including small Tim proteins, are required for an early stage of Tom40 assembly (formation of a Tom40-SAM intermediate); disrupting the IMS by swelling or small Tim mutations blocks this step. Mitochondrial swelling, in vitro import assays in small Tim mutant mitochondria, blue native PAGE The Journal of biological chemistry High 14978039
2005 Human Tom40 biogenesis requires Hsp90 for ATP-dependent cytosolic delivery to mitochondria; it forms a first stable intermediate with the outer face of the TOM complex before membrane integration and assembly, which requires Sam50 (human SAM complex); unlike fungal Tom40, human Tom40 is not stably arrested at a SAM intermediate. In vitro import assays, Hsp90 inhibitor treatment, Sam50 depletion, blue native PAGE The Journal of biological chemistry High 15644312
2000 Rat TOM40 (OM38) associates with import receptors rTOM20 and rTOM22 and small Tom proteins (OM10, OM7.5, OM5) in a ~400 kDa complex; immunodepletion of OM38 abolishes preprotein import activity of reconstituted outer membrane vesicles, confirming its essential role in the import machinery. Immunoprecipitation, blue native PAGE, reconstituted outer membrane vesicle import assay The Journal of biological chemistry High 10980201
2012 Protein kinase A (PKA) phosphorylates the Tom40 precursor in the cytosol, and this phosphorylation impairs its import into mitochondria; non-phosphorylated Tom40 precursor is efficiently imported, establishing PKA as a negative regulator of Tom40 biogenesis. In vitro kinase assay, phosphorylation-mimicking and phosphorylation-deficient mutants, in vitro import assay Molecular biology of the cell High 22419819
2010 Tom7 directly interacts with Tom40 through its transmembrane segment (shown by site-specific photocrosslinking in vivo) and with Mdm10; Tom7 recruits Mdm10 to the TOB complex to regulate timing of Tom40 release from the TOB complex for assembly into the TOM40 complex. Site-specific photocrosslinking in vivo, in vitro import assays in Tom7-depleted/overexpressing mitochondria, blue native PAGE The Journal of biological chemistry High 21036907
2010 Mdm10 regulates the timing of Tom40 release from the TOB/SAM complex: decreased Mdm10 causes Tom40 to accumulate at the TOB complex, while increased Mdm10 inhibits association of Tom40 (and other beta-barrel proteins) with the TOB complex, controlling coordinated assembly into the TOM40 complex. In vitro import assays with Mdm10-modulated mitochondria, blue native PAGE EMBO reports High 20111053
2010 Tom5 is required for a two-stage interaction of Tom40 with the SAM complex; Tom5 promotes formation of the second SAM stage and suppresses the Tom40 assembly defect of Mim1-deficient mitochondria, with Mim1's role in Tom40 biogenesis largely attributable to its role in Tom5 import. In vitro import assays in Tom5-deficient and Mim1-deficient mitochondria, blue native PAGE, genetic epistasis Molecular biology of the cell High 20668160
2014 Tom40 directly interacts with presequences on both the cis and trans sides of the beta-barrel, with presequence-interacting regions mapped by mass spectrometry; a phosphorylation site within one of these regions alters translocation kinetics along the presequence pathway. Photoaffinity labeling with modified presequence peptides, mass spectrometry mapping, phosphomimetic mutation analysis Molecular and cellular biology High 25002531
2011 Single-molecule tracking by photoactivated localization microscopy (PALM) shows Tom40 movement in the mitochondrial outer membrane is highly dynamic but confined, suggesting anchoring of the TOM complex as a whole. Single-molecule fluorescence microscopy (PALM) with Dendra2-Tom40 fusion in isolated yeast mitochondria Scientific reports Medium 22355710
2012 Electrophysiological analysis shows presequence peptide binding kinetics to the Tom40 channel are voltage-dependent: both association (k_on) and dissociation (k_off) rates increase with applied voltage, and the voltage-dependent increase in k_off provides evidence of peptide translocation through the pore. High-resolution single-channel electrophysiology in planar lipid bilayers Biophysical journal High 22225796
2014 Tom40 exhibits at least four distinct conductive levels/conformations, and substrate (presequence peptide) binding affinity is dependent on the conformational state; neither the N-terminal 51 residues nor the C-terminal 13 residues are required for channel formation or presequence interaction. Planar lipid bilayer electrophysiology with full-length and truncated recombinant Tom40 constructs The Journal of biological chemistry High 26336107
2014 PB1-F2 of influenza A virus translocates completely into the mitochondrial inner membrane space via Tom40 channels; this accumulation reduces mitochondrial membrane potential, causing fragmentation and suppression of RIG-I signaling and NLRP3 inflammasome activation. Live cell imaging, mitochondrial fractionation, Tom40 knockdown/blocking, membrane potential measurements, innate immune reporter assays Nature communications High 25140902
2019 BAP31 (ER membrane protein) forms an ER-mitochondria bridging complex with Tom40 at ER-mitochondria contact sites; this BAP31-Tom40 complex stimulates translocation of NDUFS4 from cytosol to mitochondria to support complex I activity; disruption of this complex inhibits complex I activity and oxygen consumption. Co-immunoprecipitation, subcellular fractionation, NDUFS4 localization assay, oxygen consumption measurement, BAP31 knockout Science advances High 31206022
2019 TOM40 recruits Atg2A to mitochondria-associated ER membranes (MAM) for phagophore expansion; Atg2A interacts with TOM40 via a C-terminal MAM localization domain (MLD) in a TOM70-dependent manner; inhibition of Atg2A-TOM40 interaction impairs phagophore expansion and accumulates Atg9A vesicles. Proteomic analysis (MS), Co-IP, domain deletion mapping, autophagy flux assays, Atg9A vesicle accumulation imaging Cell reports High 31412244
2013 TOM40 is significantly reduced in PD patient brains and in alpha-synuclein transgenic mice; TOM40 deficits are associated with increased mtDNA deletions, oxidative damage, and decreased energy production; lentiviral overexpression of Tom40 in alpha-synuclein transgenic mouse brain ameliorated energy deficits and oxidative burden. Laser-capture microdissection, brain homogenate analysis, lentiviral gene delivery with functional mitochondrial readouts (ATP, respiratory complexes, mtDNA deletions) PloS one High 23626796
2018 TOMM40 protein is N-myristoylated, but unlike SAMM50 and MIC19, this lipid modification is not required for TOMM40 mitochondrial targeting or membrane binding (G2A mutant localizes normally to mitochondria). In vitro and in vivo metabolic labeling, immunofluorescence microscopy, subcellular fractionation of WT vs. G2A mutant PloS one Medium 30427857
2011 Structural modeling of Tom40 from Neurospora crassa using mouse VDAC-1 as a template, combined with limited proteolysis and mass spectrometry, identified membrane topology and revealed two conserved polar slides in the pore interior, one specific to Tom40 (not VDAC) that may mediate presequence binding. Limited proteolysis combined with mass spectrometry, comparative structural modeling Biochimica et biophysica acta Medium 21888892
2014 Tom40 supports the 19 beta-strand barrel model: substituted cysteine accessibility mapping identified multiple beta-strands and protease accessibility studies showed the C-terminal end localizes to the intermembrane space. Substituted cysteine accessibility mapping (SCAM), protease accessibility assays in isolated mitochondria The Journal of biological chemistry High 24947507
2011 Human Tom40 isoforms reconstituted from recombinant protein show dominant beta-sheet secondary structure (by CD and FTIR), high thermal stability, and ion channel activity similar to Neurospora crassa Tom40 but with distinct conductivity fingerprints from VDAC proteins. Recombinant expression, CD spectroscopy, FTIR, planar lipid bilayer reconstitution The Journal of membrane biology Medium 21717124
2023 Tom40 mediates mitochondrial cholesterol transport in steroidogenic cells: cytoplasmic cholesterol-lipid complexes containing StAR move from MAM to the outer mitochondrial membrane where Tom40 interacts with StAR to facilitate cholesterol import; Tom40 absence disassembles the complex and inhibits steroidogenesis. Co-IP, Tom40 knockout, cholesterol transport assays in rat testicular tissue and MA-10 mouse Leydig cells, steroidogenesis measurements iScience Medium 37035007
2024 Mitochondria-targeted oligomeric alpha-synuclein selectively degrades TOM40 (not TOM20) via the ubiquitin-proteasome system (UPS); this TOM40 loss results in reduced mitochondrial membrane potential, mtDNA damage, and altered oxygen consumption; ectopic TOM40 supplementation or reduction of pathological alpha-synuclein ameliorates these defects. Co-IP of alpha-syn with TOM40/TOM20, UPS inhibitor experiments, Seahorse respirometry, mtDNA sequencing, TOM40 ectopic overexpression rescue Cell death & disease High 39695091
2017 TOM40 overexpression increases expression of TOM20, mitochondrial chaperone HSPA9, and PDHE1a; elevates activities of oxidative phosphorylation complexes I and IV and TCA cycle enzyme alpha-ketoglutaric acid dehydrogenase; raises mitochondrial membrane potential, cellular ATP, and respiration; and blocks Abeta-elicited decreases in these parameters. TOM40 overexpression in cell lines, western blotting for TOM complex components, enzyme activity assays, ATP measurement, membrane potential assay, Abeta challenge Biochimica et biophysica acta. Molecular basis of disease Medium 28768149
2023 TOMM40 missense variants F113L and F131L induce mitochondrial dysfunction and oxidative stress-driven activation of microglia and NLRP3 inflammasome in BV2 cells; pro-inflammatory cytokines released cause hippocampal neuron death. Cell line expression of mutant TOMM40, mitochondrial function assays, ROS measurement, NLRP3 inflammasome activation assay, cytokine measurement, neurotoxicity assay International journal of molecular sciences Medium 36835494
2025 TREM1 activation in macrophages upregulates TOMM40 transcription via the E2F1 transcription factor (validated by ChIP-PCR showing E2F1-TOMM40 gene interaction); increased TOMM40 disrupts mitophagy flux; E2F1 knockdown reverses TOMM40 upregulation and restores mitophagy. RNA-seq, ChIP-PCR, E2F1 siRNA knockdown, mitophagy assays, ROS measurement Free radical biology & medicine Medium 39793906
2018 miR-126 upregulation under heat stress reduces AUF1-mediated SP1 mRNA degradation, increasing SP1 levels which transcriptionally upregulates TOMM40; elevated TOMM40 decreases mitochondrial membrane potential and promotes cardiomyocyte apoptosis. miR-126 overexpression/inhibition, AUF1 manipulation, SP1 measurement, TOMM40 transcriptional reporter, membrane potential assay, apoptosis assay in rat cardiomyocytes Journal of molecular and cellular cardiology Medium 30296408
2023 TOMM40 and TOMM22 knockdown in skeletal myotubes impairs mitochondrial oxidative function, increases mitochondrial superoxide, reduces mitochondrial cholesterol and CoQ levels, disrupts mitochondrial dynamics/morphology, and increases mitophagy; overexpression of TOMM40 and TOMM22 in simvastatin-treated cells rescues mitochondrial dynamics but not function or lipid levels, demonstrating TOMM40's role in mitochondrial dynamics regulation. siRNA knockdown, overexpression, Seahorse respirometry, electron microscopy, mitophagy assays in C2C12 and primary human skeletal myotubes bioRxivpreprint Medium 37425714
2017 PPARγ knockdown in HepG2 cells increases TOMM40, APOE, and APOC1 mRNA levels, while low-dose PPARγ agonists (pioglitazone, rosiglitazone) decrease their transcription, establishing PPARγ as a transcriptional regulator of the TOMM40-APOE-APOC1 gene cluster. shRNA PPARγ knockdown, PPARγ agonist treatment, RT-qPCR mRNA measurement Biochimica et biophysica acta. Molecular basis of disease Medium 28065845

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Tom40 forms the hydrophilic channel of the mitochondrial import pore for preproteins [see comment]. Nature 412 9774109
2009 A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease. The pharmacogenomics journal 302 20029386
2014 Influenza A virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity. Nature communications 197 25140902
2005 Dissection of the mitochondrial import and assembly pathway for human Tom40. The Journal of biological chemistry 163 15644312
2004 Biogenesis of the protein import channel Tom40 of the mitochondrial outer membrane: intermembrane space components are involved in an early stage of the assembly pathway. The Journal of biological chemistry 149 14978039
2001 Protein import channel of the outer mitochondrial membrane: a highly stable Tom40-Tom22 core structure differentially interacts with preproteins, small tom proteins, and import receptors. Molecular and cellular biology 145 11259583
2001 Tom40, the pore-forming component of the protein-conducting TOM channel in the outer membrane of mitochondria. The Journal of cell biology 140 11402060
2013 TOM40 mediates mitochondrial dysfunction induced by α-synuclein accumulation in Parkinson's disease. PloS one 131 23626796
1999 Biogenesis of Tom40, core component of the TOM complex of mitochondria. The Journal of cell biology 128 10427088
2019 BAP31 regulates mitochondrial function via interaction with Tom40 within ER-mitochondria contact sites. Science advances 117 31206022
2011 The effect of TOMM40 poly-T length on gray matter volume and cognition in middle-aged persons with APOE ε3/ε3 genotype. Alzheimer's & dementia : the journal of the Alzheimer's Association 109 21784354
1997 Mitochondrial protein import. Tom40 plays a major role in targeting and translocation of preproteins by forming a specific binding site for the presequence. The Journal of biological chemistry 108 9228044
2019 TOM40 Targets Atg2 to Mitochondria-Associated ER Membranes for Phagophore Expansion. Cell reports 101 31412244
2011 Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease. Archives of neurology 96 21825236
2011 Genetic variants in LPL, OASL and TOMM40/APOE-C1-C2-C4 genes are associated with multiple cardiovascular-related traits. BMC medical genetics 87 21943158
2010 An inherited variable poly-T repeat genotype in TOMM40 in Alzheimer disease. Archives of neurology 87 20457951
2010 Tom7 regulates Mdm10-mediated assembly of the mitochondrial import channel protein Tom40. The Journal of biological chemistry 87 21036907
2011 Functional analysis of APOE locus genetic variation implicates regional enhancers in the regulation of both TOMM40 and APOE. Journal of human genetics 85 22089642
2003 Tom40, the import channel of the mitochondrial outer membrane, plays an active role in sorting imported proteins. The EMBO journal 85 12743032
2010 Mdm10 as a dynamic constituent of the TOB/SAM complex directs coordinated assembly of Tom40. EMBO reports 84 20111053
2014 The Broad Impact of TOM40 on Neurodegenerative Diseases in Aging. Journal of Parkinson's disease and Alzheimer's disease 83 25745640
2014 The cis-regulatory effect of an Alzheimer's disease-associated poly-T locus on expression of TOMM40 and apolipoprotein E genes. Alzheimer's & dementia : the journal of the Alzheimer's Association 74 24439168
2000 Characterization of rat TOM40, a central component of the preprotein translocase of the mitochondrial outer membrane. The Journal of biological chemistry 74 10980201
2018 DNA methylation of TOMM40-APOE-APOC2 in Alzheimer's disease. Journal of human genetics 66 29371683
2012 Biogenesis of the preprotein translocase of the outer mitochondrial membrane: protein kinase A phosphorylates the precursor of Tom40 and impairs its import. Molecular biology of the cell 64 22419819
2017 TOMM40'523 variant and cognitive decline in older persons with APOE ε3/3 genotype. Neurology 61 28108637
2010 Assembly of the mitochondrial protein import channel: role of Tom5 in two-stage interaction of Tom40 with the SAM complex. Molecular biology of the cell 56 20668160
2016 Understanding the genetics of APOE and TOMM40 and role of mitochondrial structure and function in clinical pharmacology of Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association 55 27154058
2018 The effects of the TOMM40 poly-T alleles on Alzheimer's disease phenotypes. Alzheimer's & dementia : the journal of the Alzheimer's Association 51 29524426
2014 Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936. Neurobiology of aging 51 24508314
2003 Tom40 protein import channel binds to non-native proteins and prevents their aggregation. Nature structural biology 50 14595396
2017 APOE ε4-TOMM40 '523 haplotypes and the risk of Alzheimer's disease in older Caucasian and African Americans. PloS one 48 28672022
2004 Membrane-embedded C-terminal segment of rat mitochondrial TOM40 constitutes protein-conducting pore with enriched beta-structure. The Journal of biological chemistry 48 15347672
2012 Characterization of the poly-T variant in the TOMM40 gene in diverse populations. PloS one 47 22359560
2017 The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease. Biochimica et biophysica acta. Molecular basis of disease 46 28768149
2012 A homopolymer polymorphism in the TOMM40 gene contributes to cognitive performance in aging. Alzheimer's & dementia : the journal of the Alzheimer's Association 46 22863908
2011 Phylogenetic and coevolutionary analysis of the β-barrel protein family comprised of mitochondrial porin (VDAC) and Tom40. Biochimica et biophysica acta 43 22178864
2002 Characterization of Neurospora crassa Tom40-deficient mutants and effect of specific mutations on Tom40 assembly. The Journal of biological chemistry 42 12399467
2001 Structural requirements of Tom40 for assembly into preexisting TOM complexes of mitochondria. Molecular biology of the cell 39 11359915
2023 TOMM40 Genetic Variants Cause Neuroinflammation in Alzheimer's Disease. International journal of molecular sciences 35 36835494
2018 BCL3-PVRL2-TOMM40 SNPs, gene-gene and gene-environment interactions on dyslipidemia. Scientific reports 34 29670124
2016 The TOMM40 gene rs2075650 polymorphism contributes to Alzheimer's disease in Caucasian, and Asian populations. Neuroscience letters 34 27328316
2020 TOM40 Inhibits Ovarian Cancer Cell Growth by Modulating Mitochondrial Function Including Intracellular ATP and ROS Levels. Cancers 32 32456076
2018 Biothiols and oxidative stress markers and polymorphisms of TOMM40 and APOC1 genes in Alzheimer's disease patients. Oncotarget 32 30443289
2014 Presequence recognition by the tom40 channel contributes to precursor translocation into the mitochondrial matrix. Molecular and cellular biology 32 25002531
2015 The effect of TOMM40 on spatial navigation in amnestic mild cognitive impairment. Neurobiology of aging 30 25862420
2014 Genetic variants in PVRL2-TOMM40-APOE region are associated with human longevity in a Han Chinese population. PloS one 30 24924924
2010 Biogenesis of the mitochondrial Tom40 channel in skeletal muscle from aged animals and its adaptability to chronic contractile activity. American journal of physiology. Cell physiology 30 20107041
2022 Association and interaction of TOMM40 and PVRL2 with plasma amyloid-β and Alzheimer's disease among Chinese older adults: a population-based study. Neurobiology of aging 29 35093267
2021 TOMM40 RNA Transcription in Alzheimer's Disease Brain and Its Implication in Mitochondrial Dysfunction. Genes 29 34204109
2013 The influence of APOE and TOMM40 polymorphisms on hippocampal volume and episodic memory in old age. Frontiers in human neuroscience 29 23734114
2011 TOMM40 poly-T repeat lengths, age of onset and psychosis risk in Alzheimer disease. Neurobiology of aging 29 21820212
2011 Structural elements of the mitochondrial preprotein-conducting channel Tom40 dissolved by bioinformatics and mass spectrometry. Biochimica et biophysica acta 29 21888892
2017 Neuropathologic features of TOMM40 '523 variant on late-life cognitive decline. Alzheimer's & dementia : the journal of the Alzheimer's Association 28 28624335
2012 Protein translocation through Tom40: kinetics of peptide release. Biophysical journal 28 22225796
2012 TOMM40 intron 6 poly-T length, age at onset, and neuropathology of AD in individuals with APOE ε3/ε3. Alzheimer's & dementia : the journal of the Alzheimer's Association 28 23183136
2017 The effects of PPARγ on the regulation of the TOMM40-APOE-C1 genes cluster. Biochimica et biophysica acta. Molecular basis of disease 27 28065845
2012 Promising Genetic Biomarkers of Preclinical Alzheimer's Disease: The Influence of APOE and TOMM40 on Brain Integrity. International journal of Alzheimer's disease 27 22550605
2015 Evidence of Distinct Channel Conformations and Substrate Binding Affinities for the Mitochondrial Outer Membrane Protein Translocase Pore Tom40. The Journal of biological chemistry 26 26336107
2013 Association of TOMM40 polymorphisms with late-onset Alzheimer's disease in a Northern Han Chinese population. Neuromolecular medicine 26 23288655
2013 Alzheimer's disease susceptibility genes APOE and TOMM40, and hippocampal volumes in the Lothian birth cohort 1936. PloS one 26 24260406
2006 Effect of mutations in Tom40 on stability of the translocase of the outer mitochondrial membrane (TOM) complex, assembly of Tom40, and import of mitochondrial preproteins. The Journal of biological chemistry 26 16757481
2022 Exosome mediated Tom40 delivery protects against hydrogen peroxide-induced oxidative stress by regulating mitochondrial function. PloS one 25 35951602
2018 Identification and characterization of protein N-myristoylation occurring on four human mitochondrial proteins, SAMM50, TOMM40, MIC19, and MIC25. PloS one 25 30427857
2017 Hippocampal thinning linked to longer TOMM40 poly-T variant lengths in the absence of the APOE ε4 variant. Alzheimer's & dementia : the journal of the Alzheimer's Association 25 28183529
2012 Downregulation of TOMM40 expression in the blood of Alzheimer disease subjects compared with matched controls. Journal of psychiatric research 24 22472643
2011 Single molecule tracking fluorescence microscopy in mitochondria reveals highly dynamic but confined movement of Tom40. Scientific reports 24 22355710
2013 TOMM40 polymorphisms in Italian Alzheimer's disease and frontotemporal dementia patients. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 23 23546992
2011 Levels of cerebrospinal fluid neurofilament light protein in healthy elderly vary as a function of TOMM40 variants. Experimental gerontology 23 21983493
2014 The TOMM40 poly-T rs10524523 variant is associated with cognitive performance among non-demented elderly with type 2 diabetes. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 22 25044051
2014 Are APOE ɛ genotype and TOMM40 poly-T repeat length associations with cognitive ageing mediated by brain white matter tract integrity? Translational psychiatry 21 25247594
2022 TOMM40 genetic variants associated with healthy aging and longevity: a systematic review. BMC geriatrics 19 35964003
2014 TOMM40 rs2075650 may represent a new candidate gene for vulnerability to major depressive disorder. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 18 24549102
2012 TOMM40 in Cerebral Amyloid Angiopathy Related Intracerebral Hemorrhage: Comparative Genetic Analysis with Alzheimer's Disease. Translational stroke research 17 24323865
2023 Tom40 in cholesterol transport. iScience 16 37035007
2014 The association between TOMM40 gene polymorphism and spontaneous brain activity in amnestic mild cognitive impairment. Journal of neurology 16 24838536
2013 Structural insights into proapoptotic signaling mediated by MTCH2, VDAC2, TOM40 and TOM22. Cellular signalling 16 24269536
2021 APOE, TOMM40, and sex interactions on neural network connectivity. Neurobiology of aging 15 34740077
2015 TOMM40 alterations in Alzheimer's disease over a 2-year follow-up period. Journal of Alzheimer's disease : JAD 15 25201778
2015 APOE/TOMM40 genetic loci, white matter hyperintensities, and cerebral microbleeds. International journal of stroke : official journal of the International Stroke Society 15 26310205
2013 Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms. Neuromuscular disorders : NMD 15 24103330
2012 Biochemical studies of poly-T variants in the Alzheimer's disease associated TOMM40 gene. Journal of Alzheimer's disease : JAD 15 22596268
2014 Evidence supporting the 19 β-strand model for Tom40 from cysteine scanning and protease site accessibility studies. The Journal of biological chemistry 14 24947507
2011 TOMM40 poly-T variants and cerebrospinal fluid amyloid beta levels in the elderly. Neurochemical research 14 21455713
2011 Functional refolding and characterization of two Tom40 isoforms from human mitochondria. The Journal of membrane biology 13 21717124
2024 Mitochondria-targeted oligomeric α-synuclein induces TOM40 degradation and mitochondrial dysfunction in Parkinson's disease and parkinsonism-dementia of Guam. Cell death & disease 12 39695091
2021 Bombyx mori cypovirus (BmCPV) induces PINK1-Parkin mediated mitophagy via interaction of VP4 with host Tom40. Developmental and comparative immunology 12 34450127
2017 Characterization of APOE and TOMM40 allele frequencies in the Japanese population. Alzheimer's & dementia (New York, N. Y.) 12 29124110
2012 Pleiotropy and allelic heterogeneity in the TOMM40-APOE genomic region related to clinical and metabolic features of hepatitis C infection. Human genetics 12 22898894
2021 Superior Frontal Gyrus TOMM40-APOE Locus DNA Methylation in Alzheimer's Disease. Journal of Alzheimer's disease reports 11 34113784
2018 Epigenetic upregulation of miR-126 induced by heat stress contributes to apoptosis of rat cardiomyocytes by promoting Tomm40 transcription. Journal of molecular and cellular cardiology 11 30296408
2017 Family history and TOMM40 '523 interactive associations with memory in middle-aged and Alzheimer's disease cohorts. Alzheimer's & dementia : the journal of the Alzheimer's Association 11 28549947
2015 Association of TOMM40 and SLC22A4 polymorphisms with ischemic stroke. Biomedical reports 11 26171154
2014 [TOMM40 gene polymorphism association with lipid profile]. Genetika 10 25711031
2025 TREM1 interferes with macrophage mitophagy via the E2F1-mediated TOMM40 transcription axis in rheumatoid arthritis. Free radical biology & medicine 9 39793906
2023 TOM40 regulates the progression of nasopharyngeal carcinoma through ROS-mediated AKT/mTOR and p53 signaling. Discover oncology 9 37351718
2023 Alzheimer's disease cortical morphological phenotypes are associated with TOMM40'523-APOE haplotypes. Neurobiology of aging 9 37804609
2023 TOMM40 and TOMM22 of the Translocase Outer Mitochondrial Membrane Complex rescue statin-impaired mitochondrial dynamics, morphology, and mitophagy in skeletal myotubes. bioRxiv : the preprint server for biology 8 37425714
2021 The TOMM40 '523' polymorphism in disease risk and age of symptom onset in two independent cohorts of Parkinson's disease. Scientific reports 8 33737565
2020 Matrix metalloproteinase-degraded type I collagen is associated with APOE/TOMM40 variants and preclinical dementia. Neurology. Genetics 8 33134509