Affinage

TOMM40

Mitochondrial import receptor subunit TOM40 homolog · UniProt O96008

Length
361 aa
Mass
37.9 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TOMM40 (Tom40) is the pore-forming subunit of the translocase of the outer mitochondrial membrane (TOM complex), serving as the principal channel through which nuclear-encoded preproteins enter the mitochondrion (PMID:9774109). Reconstituted Tom40 is a predominantly beta-sheet protein that assembles into an oligomeric channel of ~22-25 Å, forms a cation-selective high-conductance pore, and specifically binds mitochondrial targeting presequences (PMID:9774109, PMID:11402060, PMID:15347672). Rather than acting as a passive conduit, Tom40 actively engages translocating chains: it contacts presequences at both the cytosolic (cis) and intermembrane-space (trans) faces of its barrel, holds the precursor as it advances past the Tom20/Tom22 receptors, binds long stretches of unfolded polypeptide to suppress aggregation, and sorts precursors toward distinct downstream destinations — a function demonstrated by a single point mutation (W243R) that selectively abolishes handoff to the TIM23 complex while sparing TIM54 and outer-membrane insertion (PMID:9228044, PMID:12743032, PMID:14595396, PMID:25002531). With Tom22 it constitutes the stable functional core (general import pore) of the complex (PMID:11259583). Translocation through the channel is voltage-dependent and coupled to conformational states that tune substrate affinity (PMID:26336107, PMID:22225796). Biogenesis of Tom40 itself proceeds through an ordered multi-step pathway: Hsp90-mediated ATP-dependent cytosolic delivery, Tom20-facilitated surface binding, IMS small-Tim-dependent early steps, and sequential SAM/TOB intermediates whose progression is timed by Sam50, Tom5, Mim1, Tom7 and Mdm10, with cytosolic PKA phosphorylation of the precursor acting as an inhibitory checkpoint (PMID:10427088, PMID:15644312, PMID:14978039, PMID:21036907, PMID:20111053, PMID:20668160, PMID:22419819). Beyond canonical import, Tom40 bridges ER–mitochondria contact sites through BAP31 to support complex I subunit import and recruits the autophagy regulator Atg2A via TOM70 to drive phagophore expansion (PMID:31206022, PMID:31412244), and engages StAR to enable mitochondrial cholesterol import for steroidogenesis (PMID:37035007). Loss or obstruction of TOM40 — by alpha-synuclein-driven proteasomal degradation, viral PB1-F2 occlusion, or AD-associated missense variants — produces membrane-potential collapse, mtDNA damage and bioenergetic failure, linking the channel to Parkinson's and Alzheimer's pathology (PMID:25140902, PMID:23626796, PMID:39695091, PMID:36835494).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1997 High

    Established that Tom40, not the receptor subunits, is the component that retains a translocating presequence at the trans side of the outer membrane, defining where the precursor resides during passage.

    Evidence Chemical cross-linking of translocating preproteins to TOM subunits in isolated yeast mitochondria

    PMID:9228044

    Open questions at the time
    • Did not resolve the structural basis of presequence binding
    • Did not establish channel conductance properties
  2. 1998 High

    Resolved whether Tom40 alone forms the import channel by showing purified reconstituted Tom40 is a cation-selective ~22 Å pore that binds presequences and transports preproteins.

    Evidence Functional reconstitution of purified Tom40 into planar lipid bilayers with electrophysiology and presequence-binding assays

    PMID:9774109

    Open questions at the time
    • Oligomeric state and number of active pores per complex not defined
    • High-resolution atomic structure not determined
  3. 2001 High

    Defined the minimal stable functional core of the import pore as Tom40 plus Tom22 and showed the complex contains two coupled, simultaneously active Tom40 channels.

    Evidence Detergent stripping, preprotein cross-linking, BN-PAGE and electrophysiology of outer membrane vesicles; oligomeric channel characterization from N. crassa

    PMID:11259583 PMID:11402060

    Open questions at the time
    • Stoichiometry of pores per complex inferred electrophysiologically, not structurally
    • Roles of small Tom subunits in core function not addressed
  4. 2003 High

    Showed Tom40 is an active sorting and chaperone-like element rather than a passive tube, directing precursors to specific downstream translocases and binding extensive unfolded segments to prevent aggregation.

    Evidence Allele-specific tom40 mutant (W243R) with multiple import substrates; site-specific photocrosslinking and aggregation-suppression assays with purified Tom40

    PMID:12743032 PMID:14595396

    Open questions at the time
    • Molecular determinants of destination selectivity not mapped
    • How aggregation suppression couples to forward translocation unclear
  5. 2004 High

    Localized the preprotein-recognition and pore function to the membrane-embedded C-terminal beta-sheet half of mammalian TOM40 and defined Hsp90- and SAM-dependent steps of human Tom40 biogenesis.

    Evidence Recombinant rat TOM40 truncation with CD/FTIR, binding/translocation and electrophysiology; human in vitro import with Hsp90 inhibition and Sam50 siRNA; small-Tim-dependence in yeast

    PMID:14978039 PMID:15347672 PMID:15644312

    Open questions at the time
    • Human assembly intermediates differ from fungi and not fully resolved
    • Mechanism of Hsp90 handoff to the membrane not defined
  6. 2010 High

    Dissected the ordered SAM/TOB assembly route of Tom40, identifying Tom5, Mim1, Tom7 and Mdm10 as factors that stage and time release of Tom40 into the mature complex.

    Evidence In vitro import in deletion mutants, epistasis, in vivo photocrosslinking and BN-PAGE assembly-intermediate tracking in yeast

    PMID:12399467 PMID:20111053 PMID:20668160 PMID:21036907

    Open questions at the time
    • Quantitative kinetics of intermediate transitions not measured
    • Whether the same factor hierarchy operates in mammals not established
  7. 2012 High

    Identified a regulatory checkpoint on TOM biogenesis: cytosolic PKA phosphorylation of the Tom40 precursor blocks its import, and established voltage as a driving force for substrate translocation through the pore.

    Evidence In vitro PKA kinase assay with phospho-mutants and import reconstitution; single-channel conductance kinetics of presequence peptide pF1β

    PMID:22225796 PMID:22419819

    Open questions at the time
    • Physiological signals controlling PKA-dependent regulation unknown
    • Coupling of membrane potential to bulk preprotein import in vivo not quantified
  8. 2014 High

    Mapped presequence-interacting surfaces on both faces of the Tom40 barrel and advanced topology/beta-strand models of the channel.

    Evidence Photoaffinity labeling with MS mapping and phospho-mutant kinetics; substituted cysteine accessibility mapping and limited proteolysis topology

    PMID:24947507 PMID:25002531

    Open questions at the time
    • Beta-barrel strand number resolved only by modeling/accessibility, not crystallography
    • Dynamic rearrangement of binding sites during transit not captured
  9. 2015 High

    Demonstrated that Tom40 adopts multiple conductive conformational states with state-dependent substrate affinity, linking channel conformation to substrate recognition.

    Evidence Reconstitution of full-length and truncated recombinant Tom40 in bilayers with electrophysiology and presequence-binding kinetics

    PMID:26336107

    Open questions at the time
    • Structural identity of conductance states unknown
    • Functional relevance of conformational switching in vivo untested
  10. 2019 Medium

    Extended TOM40 function beyond bulk import to ER–mitochondria contact biology, showing it bridges BAP31 for complex I subunit import and recruits Atg2A via TOM70 for phagophore expansion.

    Evidence Co-IP, knockout and functional respirometry for BAP31; proteomic pulldown, Co-IP and autophagy readouts for Atg2A

    PMID:31206022 PMID:31412244

    Open questions at the time
    • Single-lab Co-IP-based interactions without reciprocal structural validation
    • Whether these contact-site roles are separable from canonical import unclear
  11. 2024 Medium

    Established TOM40 as a target of neurodegeneration-associated damage, showing alpha-synuclein selectively triggers its proteasomal degradation and AD variants impair it, with downstream mitochondrial and inflammatory consequences.

    Evidence alpha-Syn MTS variants, UPS inhibition, respirometry, mtDNA sequencing and rescue in neurons; AD variant expression in microglia with NLRP3/cytokine and neuron co-culture readouts; PD brain and StAR/steroidogenesis studies

    PMID:23626796 PMID:36835494 PMID:37035007 PMID:39695091

    Open questions at the time
    • Disease-relevant findings from single labs and cell/animal models
    • Direct causal link between TOMM40 variants and human disease genetics not demonstrated within these studies

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TOM40 transcription is controlled in different cell types and how this couples to mitochondrial quality control remains incompletely resolved.
  • TREM1/E2F1 and SP1/miR-126 regulatory axes rest on single-lab studies and partly Low-confidence pathway tracing
  • An atomic structure of the human channel and a unified model linking conformation, regulation and disease is lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140104 molecular carrier activity 4 GO:0005198 structural molecule activity 3 GO:0044183 protein folding chaperone 1
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 5 R-HSA-392499 Metabolism of proteins 3 R-HSA-9609507 Protein localization 3
Partners
ATG2ABAP31SAMM50STARTOMM20TOMM22TOMM5TOMM7
Complex memberships
SAM/TOB complex (assembly intermediate)TOM complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Tom40 is the pore-forming (channel-forming) subunit of the mitochondrial general import pore (TOM complex); reconstituted Tom40 forms a cation-selective, high-conductance channel (~22 Å wide) that specifically binds mitochondrial-targeting sequences and transports preproteins across the outer membrane. Functional reconstitution of purified Tom40 into planar lipid bilayers; electrophysiology; presequence-binding assays; secondary structure analysis (beta-sheet predominant) Nature High 9774109
1997 Tom40 directly contacts translocating presequences both at an early (cis) surface stage and at the trans side of the outer membrane; chemical cross-linking shows the presequence loses contact with Tom20/Tom22 as it advances but remains associated with Tom40, identifying Tom40 as a major component of the trans presequence-binding site. Chemical cross-linking of translocating preproteins to TOM complex subunits in isolated yeast mitochondria The Journal of biological chemistry High 9228044
2001 Tom40 and Tom22 together constitute the stable functional core of the general import pore (GIP) complex; together they hold translocating preproteins even under stringent detergent conditions, and purified GIP exhibits two coupled conductance states each corresponding to a single Tom40 channel, suggesting the complex contains two simultaneously active pores. Urea/alkaline treatment of the TOM complex; preprotein cross-linking; electrophysiology of isolated outer membrane vesicles; Blue Native PAGE Molecular and cellular biology High 11259583
2001 Isolated Tom40 from Neurospora crassa forms a high-conductance channel in an oligomeric ~350 kDa complex; presequence peptides specifically interact with Tom40 reconstituted into planar lipid bilayers and decrease ion flow in a voltage-dependent manner; EM reveals a pore ~2.5 nm in diameter. Purification of Tom40 from the TOM core complex; circular dichroism and FTIR spectroscopy; planar lipid bilayer electrophysiology; electron microscopy The Journal of cell biology High 11402060
1999 Tom40 biogenesis involves import receptor Tom20 at the initial surface-binding step (Tom20 stimulates both binding and membrane insertion of the Tom40 precursor), followed by partial insertion into the outer membrane, and finally assembly into pre-existing TOM complexes; the N-terminal segment is required for assembly into the complex but not for targeting to the outer membrane. In vitro import assay with isolated yeast mitochondria; deletion mutagenesis of Tom40 precursor; antibody-depletion of Tom20 The Journal of cell biology High 10427088
2003 Tom40 is not a passive pore; a single point mutation (W243R) in Tom40 selectively abolishes transfer of preproteins to the TIM23 complex without affecting transfer to the TIM54 complex or outer membrane protein insertion, demonstrating that Tom40 actively sorts precursor proteins to different sub-mitochondrial destinations. Genetic screen of tom40 mutant library in yeast; in vitro import assays into mitochondria with distinct preprotein substrates The EMBO journal High 12743032
2003 Tom40 binds non-native/unfolded proteins and suppresses their aggregation; site-specific photocrosslinking shows up to 90 residues of an unfolded translocating precursor are simultaneously associated with Tom40; a denatured protein bound inside the Tom40 channel blocks further protein import into mitochondria. Site-specific photocrosslinking; aggregation suppression assay with purified Tom40; import competition assay Nature structural biology High 14595396
2004 The membrane-embedded C-terminal half of rat TOM40 constitutes the preprotein-recognition domain and pore; it forms ~62% beta-sheet structure, binds preprotein with high affinity through initial ionic then salt-resistant non-ionic interactions, partially translocates a matrix-targeted precursor, and exhibits presequence-sensitive cation-selective channel activity. Expression and refolding of recombinant rat TOM40 and C-terminal truncation (rTOM40ΔN165); CD and FTIR spectroscopy; preprotein binding and translocation assays; liposome reconstitution and electrophysiology; limited proteolysis The Journal of biological chemistry High 15347672
2004 Human Tom40 biogenesis requires Hsp90 for cytosolic delivery to mitochondria in an ATP-dependent manner; the precursor first forms a stable intermediate with the outer face of the existing TOM complex before membrane integration; depletion of human Sam50 reduces Tom40 assembly, but unlike in fungi, human Tom40 is not stably arrested at a SAM intermediate. In vitro import assay with human mitochondria; ATP depletion and Hsp90 inhibition; siRNA depletion of Sam50; Blue Native PAGE to track assembly intermediates The Journal of biological chemistry High 15644312
2004 Small Tim proteins of the mitochondrial intermembrane space (IMS) are required for an early stage of the Tom40 import/assembly pathway preceding formation of a Tom40–SAM complex intermediate; opening the IMS by swelling or disrupting small Tim proteins blocks this early step. Mitochondrial swelling to open IMS; import assays in mutant yeast mitochondria lacking small Tim proteins; Blue Native PAGE to monitor assembly intermediates The Journal of biological chemistry High 14978039
2005 Conserved regions near the N terminus (residues 51–60) and C terminus (residues 321–323) of Neurospora crassa Tom40 are required for assembly beyond a 250 kDa intermediate into the 400 kDa TOM complex; a tom40 null is lethal; mitochondria with reduced Tom40 show reduced levels of Tom22 and Tom6. Generation of tom40 null mutant in N. crassa heterokaryon; in vitro import assay; deletion and alanine-substitution mutagenesis; Blue Native PAGE The Journal of biological chemistry High 12399467
2012 Protein kinase A (PKA) phosphorylates the precursor form of Tom40 in the cytosol; the phosphorylated precursor is impaired in import into mitochondria, whereas the non-phosphorylated precursor is efficiently imported, establishing a regulatory mechanism that controls TOM complex biogenesis. In vitro kinase assay with PKA; phospho-mutant Tom40 constructs; in vitro import assay into isolated yeast mitochondria Molecular biology of the cell High 22419819
2010 Tom7 directly interacts with Tom40 through its transmembrane segment (demonstrated by site-specific photocrosslinking in vivo) and with Mdm10; Tom7 recruits Mdm10 to the TOB/SAM complex, facilitating coordinated and timely release of Tom40 from the TOB complex for assembly into the mature TOM40 complex. Site-specific photocrosslinking in vivo; in vitro import assay in Tom7- and Mdm10-depleted mitochondria; Blue Native PAGE The Journal of biological chemistry High 21036907
2010 Mdm10 level within the TOB/SAM complex controls the timing of Tom40 release: decreased Mdm10 causes accumulation of imported Tom40 at the TOB stage, while increased Mdm10 inhibits association of Tom40 (and other beta-barrel proteins) with the TOB complex, demonstrating Mdm10 as a dynamic regulator of Tom40 assembly kinetics. Conditional alteration of Mdm10 levels at the TOB (not MMM1) complex; in vitro import assay; Blue Native PAGE EMBO reports High 20111053
2010 Tom5 directly associates with the Tom40 precursor at a second stage of the SAM complex interaction, promoting progression from the first SAM stage to a Tom5–Tom40 SAM intermediate; Mim1 affects Tom40 biogenesis largely through its role in Tom5 import rather than through a direct effect on Tom40. In vitro import assay in tom5Δ and mim1Δ mitochondria; suppression of mim1Δ assembly defect by Tom5 overexpression; Blue Native PAGE to define assembly stages Molecular biology of the cell High 20668160
2014 Tom40 directly contacts presequence peptides at both the cytosolic and IMS faces of the beta-barrel; photoaffinity labeling mapped the presequence-interacting regions to both sides of the barrel; a phosphorylation site within one presequence-interacting region of Tom40 alters translocation kinetics; this region can function independently of the established Tom22 trans-binding domain during matrix import. Photoaffinity labeling with modified presequence peptides; mass spectrometry mapping; phospho-mutant analysis of translocation kinetics Molecular and cellular biology High 25002531
2015 Recombinant Tom40 (from Candida glabrata) exhibits at least four distinct conductive levels in planar lipid bilayers; all truncated constructs lacking N-terminal (first 51 aa) or C-terminal (last 13 aa) domains still form channels and interact with presequence peptides in a concentration- and voltage-dependent manner; substrate binding affinity differs between conformational states, suggesting Tom40 conformation influences substrate recognition during transport. Purification and reconstitution of recombinant full-length and truncated Tom40 in planar lipid bilayers; electrophysiology; presequence peptide-binding kinetics The Journal of biological chemistry High 26336107
2012 Protein translocation through the Tom40 channel is voltage-dependent: rates of association (kon) and dissociation (koff) of a mitochondrial presequence peptide both increase with applied voltage; the increase in koff with voltage provides direct electrophysiological evidence for peptide translocation through the pore rather than mere blocking. High-resolution single-channel ion conductance measurements with presequence peptide pF1β in planar lipid bilayers; kinetic analysis Biophysical journal High 22225796
2014 Evidence supporting a 19 beta-strand barrel model for Tom40: substituted cysteine accessibility mapping in isolated mitochondria identified multiple membrane-spanning beta-strands consistent with the model; protease accessibility studies placed the C-terminal end of Tom40 in the IMS. Substituted cysteine accessibility mapping (SCAM); limited proteolysis of isolated mitochondria; topology analysis The Journal of biological chemistry Medium 24947507
2011 Tom40 topology determined by limited proteolysis coupled with mass spectrometry reveals accessible cleavage sites consistent with a beta-barrel model; structural modeling based on mouse VDAC-1 template identifies two conserved polar slides in the pore interior, one potentially involved in pore-helix positioning and one (specific to Tom40, absent in VDAC) potentially involved in mitochondrial presequence binding. Limited proteolysis of Neurospora crassa Tom40 from isolated mitochondria; mass spectrometry; comparative structural modeling Biochimica et biophysica acta Medium 21888892
2011 Individual Tom40 molecules in the mitochondrial outer membrane undergo highly dynamic but spatially confined diffusion, as shown by single-molecule tracking; this confinement suggests the TOM complex is anchored as a whole within the outer membrane. Single-molecule tracking fluorescence microscopy using photoconvertible Dendra2-tagged Tom40 in intact isolated yeast mitochondria; PALM imaging Scientific reports Medium 22355710
2014 Influenza A viral protein PB1-F2 translocates completely into the mitochondrial inner membrane space via Tom40 channels; this translocation requires the C-terminal polypeptide of PB1-F2, reduces mitochondrial membrane potential, causes mitochondrial fragmentation, and suppresses RIG-I signaling and NLRP3 inflammasome activation. Expression of PB1-F2 variants in host cells; subcellular fractionation; mitochondrial membrane potential measurement; co-localization; functional innate immunity assays Nature communications Medium 25140902
2019 Tom40 interacts with the ER membrane protein BAP31 at ER-mitochondria contact sites (MAM); this BAP31–Tom40 bridging complex stimulates translocation of the complex I subunit NDUFS4 from cytosol to mitochondria; disruption of the BAP31–Tom40 complex reduces complex I activity and oxygen consumption. Co-immunoprecipitation; subcellular fractionation; BAP31 knockout; measurement of mitochondrial complex I activity and oxygen consumption; NDUFS4 localization assay Science advances Medium 31206022
2019 TOM40 serves as a direct binding partner of the autophagy regulator Atg2A via Atg2A's C-terminal MAM localization domain (MLD); this TOM40 interaction (requiring TOM receptor TOM70) recruits Atg2A to MAM for phagophore expansion; inhibition of the Atg2A–TOM40 interaction impairs phagophore expansion and accumulates Atg9A vesicles near autophagic structures. Proteomic pulldown identifying TOM40 as MLD-interacting partner; Co-IP validation; TOM70 dependency assay; phagophore expansion and Atg9A localization readouts Cell reports Medium 31412244
2018 Human TOMM40 protein undergoes N-myristoylation at its N-terminal glycine; however, unlike SAMM50 and MIC19, N-myristoylation of TOMM40 is NOT required for its mitochondrial targeting or membrane binding—a G2A non-myristoylatable mutant localizes normally to mitochondria. In vitro and in vivo metabolic labeling; immunofluorescence microscopy; subcellular fractionation; G2A mutagenesis PloS one Medium 30427857
2013 TOM40 is significantly reduced in brain of Parkinson's disease patients and in alpha-synuclein transgenic mice; TOM40 deficits correlate with increased mtDNA deletions, oxidative DNA damage, and decreased complex I proteins; lentiviral overexpression of Tom40 in alpha-Syn transgenic mouse brain ameliorates energy deficits and oxidative burden. Western blot and laser-capture microdissection of human PD and mouse brains; lentiviral TOM40 overexpression in vivo; measurement of mtDNA deletions, oxidative damage, and respiratory chain complexes PloS one Medium 23626796
2024 Oligomeric alpha-synuclein accumulation in neurons selectively degrades TOM40 protein (but not TOM20) via the ubiquitin-proteasome system; mitochondria-targeted alpha-synuclein is required for TOM40 degradation; TOM40 loss results in reduced mitochondrial membrane potential, accumulated mtDNA damage/mutations, and altered oxygen consumption; ectopic TOM40 supplementation rescues these mitochondrial defects. Expression of alpha-Syn variants with/without MTS in cultured neurons; UPS inhibitor treatment; Seahorse respirometry; mtDNA sequencing; TOM40 overexpression rescue; PD patient-derived cells Cell death & disease Medium 39695091
2023 Tom40 interacts with StAR protein at the outer mitochondrial membrane and is central to mitochondrial cholesterol transport for steroidogenesis; absence of Tom40 disassembles the StAR-containing complex and inhibits cholesterol transport into mitochondria and steroidogenesis. Co-immunoprecipitation of Tom40 with StAR in rat testicular tissue and MA-10 cells; Tom40 ablation with measurement of cholesterol transport and steroid production iScience Medium 37035007
2017 TOM40 overexpression in cells increases expression of TOM20, the mitochondrial chaperone HSPA9, and PDHE1a; increases activities of respiratory chain complexes I and IV and TCA enzyme alpha-ketoglutaric acid dehydrogenase; elevates mitochondrial membrane potential, total cellular ATP, and respiration; and blocks Aβ-elicited decreases in mitochondrial membrane potential, ATP levels, and cell viability. Stable TOM40-overexpressing cell lines; MitoTracker staining; enzyme activity assays; ATP measurement; membrane potential measurement; Aβ treatment and cell viability assay Biochimica et biophysica acta. Molecular basis of disease Medium 28768149
2020 TOM40 knockdown in ovarian cancer cells decreases proliferation and reduces tumor burden in xenograft mice; TOM40 expression positively correlates with intracellular ATP levels; TOM40 knockdown increases ROS and decreases mitochondrial membrane potential, activating AMPK (though AMPK activity does not mediate growth inhibition). siRNA knockdown; in vivo xenograft model; ATP and ROS measurement; AMPK activity assay Cancers Medium 32456076
2023 AD-associated TOMM40 missense variants F113L and F131L induce mitochondrial dysfunction and oxidative stress when expressed in BV2 microglial cells, leading to NLRP3 inflammasome activation and release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) that cause hippocampal neuron death. Transfection of mutant TOMM40 in BV2 cells; mitochondrial function assays; NLRP3 inflammasome activation measurement; cytokine measurement; neuron co-culture viability assay International journal of molecular sciences Medium 36835494
2025 TREM1 activation in macrophages upregulates TOMM40 transcription via the transcription factor E2F1; ChIP-PCR demonstrates E2F1 binds the TOMM40 gene promoter region in TREM1-overexpressing cells; E2F1 knockdown reverses TOMM40 upregulation, restores mitophagy flux, and reduces ROS in TREM1-overexpressing macrophages. ChIP-PCR; RNA-seq; E2F1 siRNA knockdown; TREM1 overexpression; mitophagy measurement (PINK1, Parkin, LC3B); ROS measurement Free radical biology & medicine Medium 39793906
2023 Knockdown of TOMM40 and TOMM22 in skeletal cell myotubes impairs mitochondrial oxidative function, increases mitochondrial superoxide, reduces mitochondrial cholesterol and CoQ levels, disrupts mitochondrial dynamics and morphology, and increases mitophagy; overexpression of TOMM40 and TOMM22 in simvastatin-treated cells rescues mitochondrial dynamics and morphology defects but not cholesterol/CoQ levels. siRNA knockdown and overexpression in C2C12 and primary human myotubes; Seahorse respirometry; TEM; MitoSOX; cholesterol and CoQ measurement; mitophagy assay; simvastatin treatment bioRxivpreprint Medium 37425714
2018 Heat stress-induced upregulation of miR-126 reduces AUF1-mediated degradation of SP1 mRNA, increasing SP1 levels which drive TOMM40 transcription; elevated TOMM40 in turn decreases mitochondrial membrane potential and promotes cardiomyocyte apoptosis; the miR-126 upregulation is caused by TET2-mediated promoter demethylation. miR-126 overexpression/inhibition; AUF1 manipulation; SP1 overexpression; TOMM40 knockdown/overexpression; mitochondrial membrane potential measurement; apoptosis assay in rat cardiomyocytes Journal of molecular and cellular cardiology Low 30296408

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 413 9774109
2009 A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease. The pharmacogenomics journal 307 20029386
2014 Influenza A virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity. Nature communications 200 25140902
2005 Dissection of the mitochondrial import and assembly pathway for human Tom40. The Journal of biological chemistry 164 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 150 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 147 11259583
2001 Tom40, the pore-forming component of the protein-conducting TOM channel in the outer membrane of mitochondria. The Journal of cell biology 141 11402060
2013 TOM40 mediates mitochondrial dysfunction induced by α-synuclein accumulation in Parkinson's disease. PloS one 132 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 119 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 103 31412244
2011 Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease. Archives of neurology 96 21825236
2011 Functional analysis of APOE locus genetic variation implicates regional enhancers in the regulation of both TOMM40 and APOE. Journal of human genetics 88 22089642
2010 Tom7 regulates Mdm10-mediated assembly of the mitochondrial import channel protein Tom40. The Journal of biological chemistry 88 21036907
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
2014 The Broad Impact of TOM40 on Neurodegenerative Diseases in Aging. Journal of Parkinson's disease and Alzheimer's disease 85 25745640
2010 Mdm10 as a dynamic constituent of the TOB/SAM complex directs coordinated assembly of Tom40. EMBO reports 85 20111053
2003 Tom40, the import channel of the mitochondrial outer membrane, plays an active role in sorting imported proteins. The EMBO journal 85 12743032
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 63 28108637
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 57 27154058
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 57 20668160
2018 The effects of the TOMM40 poly-T alleles on Alzheimer's disease phenotypes. Alzheimer's & dementia : the journal of the Alzheimer's Association 52 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
2017 APOE ε4-TOMM40 '523 haplotypes and the risk of Alzheimer's disease in older Caucasian and African Americans. PloS one 50 28672022
2003 Tom40 protein import channel binds to non-native proteins and prevents their aggregation. Nature structural biology 50 14595396
2004 Membrane-embedded C-terminal segment of rat mitochondrial TOM40 constitutes protein-conducting pore with enriched beta-structure. The Journal of biological chemistry 49 15347672
2017 The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease. Biochimica et biophysica acta. Molecular basis of disease 47 28768149
2012 Characterization of the poly-T variant in the TOMM40 gene in diverse populations. PloS one 47 22359560
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 45 22178864
2002 Characterization of Neurospora crassa Tom40-deficient mutants and effect of specific mutations on Tom40 assembly. The Journal of biological chemistry 42 12399467
2023 TOMM40 Genetic Variants Cause Neuroinflammation in Alzheimer's Disease. International journal of molecular sciences 39 36835494
2001 Structural requirements of Tom40 for assembly into preexisting TOM complexes of mitochondria. Molecular biology of the cell 39 11359915
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
2018 Biothiols and oxidative stress markers and polymorphisms of TOMM40 and APOC1 genes in Alzheimer's disease patients. Oncotarget 33 30443289
2014 Presequence recognition by the tom40 channel contributes to precursor translocation into the mitochondrial matrix. Molecular and cellular biology 33 25002531
2020 TOM40 Inhibits Ovarian Cancer Cell Growth by Modulating Mitochondrial Function Including Intracellular ATP and ROS Levels. Cancers 32 32456076
2015 The effect of TOMM40 on spatial navigation in amnestic mild cognitive impairment. Neurobiology of aging 32 25862420
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 31 35093267
2021 TOMM40 RNA Transcription in Alzheimer's Disease Brain and Its Implication in Mitochondrial Dysfunction. Genes 31 34204109
2014 Genetic variants in PVRL2-TOMM40-APOE region are associated with human longevity in a Han Chinese population. PloS one 31 24924924
2017 Neuropathologic features of TOMM40 '523 variant on late-life cognitive decline. Alzheimer's & dementia : the journal of the Alzheimer's Association 30 28624335
2013 The influence of APOE and TOMM40 polymorphisms on hippocampal volume and episodic memory in old age. Frontiers in human neuroscience 30 23734114
2011 Structural elements of the mitochondrial preprotein-conducting channel Tom40 dissolved by bioinformatics and mass spectrometry. Biochimica et biophysica acta 30 21888892
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
2011 TOMM40 poly-T repeat lengths, age of onset and psychosis risk in Alzheimer disease. Neurobiology of aging 29 21820212
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
2013 Association of TOMM40 polymorphisms with late-onset Alzheimer's disease in a Northern Han Chinese population. Neuromolecular medicine 27 23288655
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
2022 Exosome mediated Tom40 delivery protects against hydrogen peroxide-induced oxidative stress by regulating mitochondrial function. PloS one 26 35951602
2018 Identification and characterization of protein N-myristoylation occurring on four human mitochondrial proteins, SAMM50, TOMM40, MIC19, and MIC25. PloS one 26 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 26 28183529
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 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
2012 Downregulation of TOMM40 expression in the blood of Alzheimer disease subjects compared with matched controls. Journal of psychiatric research 25 22472643
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 24 23546992
2011 Single molecule tracking fluorescence microscopy in mitochondria reveals highly dynamic but confined movement of Tom40. Scientific reports 24 22355710
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
2022 TOMM40 genetic variants associated with healthy aging and longevity: a systematic review. BMC geriatrics 21 35964003
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
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 18 24323865
2023 Tom40 in cholesterol transport. iScience 17 37035007
2013 Structural insights into proapoptotic signaling mediated by MTCH2, VDAC2, TOM40 and TOM22. Cellular signalling 17 24269536
2014 The association between TOMM40 gene polymorphism and spontaneous brain activity in amnestic mild cognitive impairment. Journal of neurology 16 24838536
2024 Mitochondria-targeted oligomeric α-synuclein induces TOM40 degradation and mitochondrial dysfunction in Parkinson's disease and parkinsonism-dementia of Guam. Cell death & disease 15 39695091
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
2014 Evidence supporting the 19 β-strand model for Tom40 from cysteine scanning and protease site accessibility studies. The Journal of biological chemistry 15 24947507
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
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 14 21717124
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
2025 TREM1 interferes with macrophage mitophagy via the E2F1-mediated TOMM40 transcription axis in rheumatoid arthritis. Free radical biology & medicine 10 39793906
2014 [TOMM40 gene polymorphism association with lipid profile]. Genetika 10 25711031
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
2012 The Tom40 assembly process probed using the attachment of different intramitochondrial sorting signals. Molecular biology of the cell 8 22933571

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