TOMM70

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005741 mitochondrial outer membrane	IBA GO_REF:0000033	ACCEPT	Summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor with a cytosol-facing TPR receptor domain. Supporting Evidence: file:human/TOMM70/TOMM70-deep-research-falcon.md TOMM70 is anchored in the outer mitochondrial membrane (OMM) with its receptor domain facing the cytosol.
GO:0008320 protein transmembrane transporter activity	IBA GO_REF:0000033	ACCEPT	Summary: Accepted as TOMM70 contribution to TOM-dependent protein transmembrane transport. TOMM70 is a receptor/adaptor, not the pore-forming subunit, but it contributes to the TOM complex import activity. Supporting Evidence: file:human/TOMM70/TOMM70-deep-research-falcon.md TOMM70 is best understood as a surface receptor/adaptor of the TOM (translocase of the outer membrane) import gateway
GO:0030150 protein import into mitochondrial matrix	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Broadly valid as a TOM-pathway outcome, but TOMM70 is best described as an outer-membrane receptor/adaptor rather than the matrix import pore or motor. Reason: Matrix import is one TOM-dependent route; TOMM70 has a more specific receptor/adaptor role for chaperone-bound precursors.
GO:0030943 mitochondrion targeting sequence binding	IBA GO_REF:0000033	ACCEPT	Summary: Supported. TOMM70 recognizes mitochondrial precursor proteins, especially hydrophobic internal-signal substrates delivered by Hsp70/Hsp90 chaperones. Supporting Evidence: file:human/TOMM70/TOMM70-deep-research-falcon.md Cytosolic Hsp70/Hsp90 chaperones bind newly synthesized hydrophobic precursors to prevent aggregation and deliver them to TOMM70
GO:0045039 protein insertion into mitochondrial inner membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Reasonable as a pathway-level consequence for carrier/internal-signal precursor delivery, but TOMM70 does not catalyze inner membrane insertion itself. Reason: TOMM70 acts upstream at the outer membrane before substrates are handed to downstream inner-membrane import machinery.
GO:0005741 mitochondrial outer membrane	IEA GO_REF:0000120	ACCEPT	Summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor with a cytosol-facing TPR receptor domain.
GO:0005515 protein binding	IPI PMID:32353859 A SARS-CoV-2 protein interaction map reveals targets for dru...	REMOVE	Summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1 signaling. Reason: Replace generic protein binding curation with specific adaptor, receptor, TOM complex, and pathway annotations.
GO:0005515 protein binding	IPI PMID:32728199 SARS-CoV-2 Orf9b suppresses type I interferon responses by t...	REMOVE	Summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1 signaling. Reason: Replace generic protein binding curation with specific adaptor, receptor, TOM complex, and pathway annotations.
GO:0005515 protein binding	IPI PMID:33060197 Comparative host-coronavirus protein interaction networks re...	REMOVE	Summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1 signaling. Reason: Replace generic protein binding curation with specific adaptor, receptor, TOM complex, and pathway annotations.
GO:0005515 protein binding	IPI PMID:33845483 Multilevel proteomics reveals host perturbations by SARS-CoV...	REMOVE	Summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1 signaling. Reason: Replace generic protein binding curation with specific adaptor, receptor, TOM complex, and pathway annotations.
GO:0005515 protein binding	IPI PMID:33990585 Crystal structure of SARS-CoV-2 Orf9b in complex with human ...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1 signaling. Reason: The interaction is documented, but generic protein binding should be superseded by specific adaptor, receptor, TOM complex, and pathway annotations.
GO:0005515 protein binding	IPI PMID:34232536 Interactomes of SARS-CoV-2 and human coronaviruses reveal ho...	REMOVE	Summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1 signaling. Reason: Replace generic protein binding curation with specific adaptor, receptor, TOM complex, and pathway annotations.
GO:0005515 protein binding	IPI PMID:34502139 Phosphorylation of SARS-CoV-2 Orf9b Regulates Its Targeting ...	REMOVE	Summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1 signaling. Reason: Replace generic protein binding curation with specific adaptor, receptor, TOM complex, and pathway annotations.
GO:0005515 protein binding	IPI PMID:34942634 Evolution of enhanced innate immune evasion by SARS-CoV-2.	REMOVE	Summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1 signaling. Reason: Replace generic protein binding curation with specific adaptor, receptor, TOM complex, and pathway annotations.
GO:0005515 protein binding	IPI PMID:36217030 A comprehensive SARS-CoV-2-human protein-protein interactome...	REMOVE	Summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1 signaling. Reason: Replace generic protein binding curation with specific adaptor, receptor, TOM complex, and pathway annotations.
GO:0005739 mitochondrion	IEA GO_REF:0000120	MARK AS OVER ANNOTATED	Summary: Correct but too general. TOMM70 is specifically an outer mitochondrial membrane TOM receptor/adaptor. Reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
GO:0030150 protein import into mitochondrial matrix	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Broadly valid as a TOM-pathway outcome, but TOMM70 is best described as an outer-membrane receptor/adaptor rather than the matrix import pore or motor. Reason: Matrix import is one TOM-dependent route; TOMM70 has a more specific receptor/adaptor role for chaperone-bound precursors.
GO:0061052 negative regulation of cell growth involved in cardiac muscle cell development	IEA GO_REF:0000107	REMOVE	Summary: Automatic orthology transfer is not supported by the TOMM70 literature synthesis as a direct function of this gene product. Reason: Developmental/thyroxine response terms overreach beyond TOMM70's demonstrated receptor/adaptor and signaling roles.
GO:0097068 response to thyroxine	IEA GO_REF:0000107	REMOVE	Summary: Automatic orthology transfer is not supported by the TOMM70 literature synthesis as a direct function of this gene product. Reason: Developmental/thyroxine response terms overreach beyond TOMM70's demonstrated receptor/adaptor and signaling roles.
GO:1903749 positive regulation of protein localization to mitochondrion	IEA GO_REF:0000107	ACCEPT	Summary: Supported broad process annotation. TOMM70 promotes mitochondrial localization/import of precursor proteins through its receptor/adaptor role.
GO:0005739 mitochondrion	IDA GO_REF:0000052	MARK AS OVER ANNOTATED	Summary: Correct but too general. TOMM70 is specifically an outer mitochondrial membrane TOM receptor/adaptor. Reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
GO:0030150 protein import into mitochondrial matrix	TAS PMID:15644312 Dissection of the mitochondrial import and assembly pathway ...	KEEP AS NON CORE	Summary: Broadly valid as a TOM-pathway outcome, but TOMM70 is best described as an outer-membrane receptor/adaptor rather than the matrix import pore or motor. Reason: Matrix import is one TOM-dependent route; TOMM70 has a more specific receptor/adaptor role for chaperone-bound precursors.
GO:0005741 mitochondrial outer membrane	NAS PMID:18331822 Identification of Tom5 and Tom6 in the preprotein translocas...	ACCEPT	Summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor with a cytosol-facing TPR receptor domain.
GO:0045040 protein insertion into mitochondrial outer membrane	NAS PMID:18331822 Identification of Tom5 and Tom6 in the preprotein translocas...	MODIFY	Summary: The annotation captures mitochondrial protein import context but overstates TOMM70 as an outer-membrane insertase. Reason: TOMM70 is a receptor/adaptor for precursor targeting/import, not the SAM/outer-membrane insertion machinery. Proposed replacements: protein localization to mitochondrion
GO:0140596 TOM complex	NAS PMID:18331822 Identification of Tom5 and Tom6 in the preprotein translocas...	ACCEPT	Summary: Correct and specific. TOMM70 is a TOM-complex receptor component rather than an independent pore-forming subunit.
GO:0005741 mitochondrial outer membrane	EXP PMID:20628368 Tom70 mediates activation of interferon regulatory factor 3 ...	ACCEPT	Summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor with a cytosol-facing TPR receptor domain.
GO:0005741 mitochondrial outer membrane	EXP PMID:25609812 Tom70 mediates Sendai virus-induced apoptosis on mitochondri...	ACCEPT	Summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor with a cytosol-facing TPR receptor domain.
GO:0005741 mitochondrial outer membrane	EXP PMID:33723040 Toxoplasma gondii association with host mitochondria require...	ACCEPT	Summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor with a cytosol-facing TPR receptor domain.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	MARK AS OVER ANNOTATED	Summary: Correct but too general. TOMM70 is specifically an outer mitochondrial membrane TOM receptor/adaptor. Reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
GO:0005515 protein binding	IPI PMID:35391620 The role of the individual TOM subunits in the association o...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1 signaling. Reason: The interaction is documented, but generic protein binding should be superseded by specific adaptor, receptor, TOM complex, and pathway annotations.
GO:0030674 protein-macromolecule adaptor activity	IDA PMID:20628368 Tom70 mediates activation of interferon regulatory factor 3 ...	ACCEPT	Summary: Accepted. TOMM70 functions as a receptor/adaptor for chaperone-bound mitochondrial precursor proteins and also as a MAVS-linked signaling scaffold. Supporting Evidence: file:human/TOMM70/TOMM70-deep-research-falcon.md TOMM70 is best understood as a surface receptor/adaptor of the TOM (translocase of the outer membrane) import gateway
GO:0031966 mitochondrial membrane	IDA PMID:20628368 Tom70 mediates activation of interferon regulatory factor 3 ...	MARK AS OVER ANNOTATED	Summary: Correct but too broad. The specific supported localization is mitochondrial outer membrane, not generic mitochondrial membrane. Reason: Subsumed by mitochondrial outer membrane annotations.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-5205661	ACCEPT	Summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor with a cytosol-facing TPR receptor domain.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-9685281	ACCEPT	Summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor with a cytosol-facing TPR receptor domain.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-9709663	ACCEPT	Summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor with a cytosol-facing TPR receptor domain.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-9709787	ACCEPT	Summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor with a cytosol-facing TPR receptor domain.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-9709842	ACCEPT	Summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor with a cytosol-facing TPR receptor domain.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-9709852	ACCEPT	Summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor with a cytosol-facing TPR receptor domain.
GO:0002218 activation of innate immune response	IDA PMID:20628368 Tom70 mediates activation of interferon regulatory factor 3 ...	KEEP AS NON CORE	Summary: Supported in the antiviral MAVS/IRF3 literature, but this is a context-specific signaling role rather than TOMM70's core mitochondrial import function. Reason: Non-core signaling/adaptor role in antiviral innate immune response.
GO:0002230 positive regulation of defense response to virus by host	IDA PMID:20628368 Tom70 mediates activation of interferon regulatory factor 3 ...	KEEP AS NON CORE	Summary: Supported in the antiviral MAVS/IRF3 literature, but this is a context-specific signaling role rather than TOMM70's core mitochondrial import function. Reason: Non-core signaling/adaptor role in antiviral innate immune response.
GO:0005515 protein binding	IPI PMID:20628368 Tom70 mediates activation of interferon regulatory factor 3 ...	REMOVE	Summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1 signaling. Reason: Replace generic protein binding curation with specific adaptor, receptor, TOM complex, and pathway annotations.
GO:0005515 protein binding	IPI PMID:25609812 Tom70 mediates Sendai virus-induced apoptosis on mitochondri...	REMOVE	Summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1 signaling. Reason: Replace generic protein binding curation with specific adaptor, receptor, TOM complex, and pathway annotations.
GO:0005739 mitochondrion	IDA PMID:20628368 Tom70 mediates activation of interferon regulatory factor 3 ...	MARK AS OVER ANNOTATED	Summary: Correct but too general. TOMM70 is specifically an outer mitochondrial membrane TOM receptor/adaptor. Reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
GO:0005739 mitochondrion	IDA PMID:25609812 Tom70 mediates Sendai virus-induced apoptosis on mitochondri...	MARK AS OVER ANNOTATED	Summary: Correct but too general. TOMM70 is specifically an outer mitochondrial membrane TOM receptor/adaptor. Reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
GO:0032728 positive regulation of interferon-beta production	IDA PMID:20628368 Tom70 mediates activation of interferon regulatory factor 3 ...	KEEP AS NON CORE	Summary: Supported in the antiviral MAVS/IRF3 literature, but this is a context-specific signaling role rather than TOMM70's core mitochondrial import function. Reason: Non-core signaling/adaptor role in antiviral innate immune response. Supporting Evidence: file:human/TOMM70/TOMM70-deep-research-falcon.md TOMM70 is described as participating in antiviral innate immune signaling by acting as a receptor/scaffold for MAVS-associated signaling
GO:0042981 regulation of apoptotic process	IDA PMID:25609812 Tom70 mediates Sendai virus-induced apoptosis on mitochondri...	KEEP AS NON CORE	Summary: Supported for Sendai virus-induced TOMM70/Hsp90/IRF3/BAX apoptosis context, but it is a secondary signaling phenotype. Reason: Context-specific antiviral/apoptosis role rather than primary mitochondrial import function.
GO:0098586 cellular response to virus	IDA PMID:25609812 Tom70 mediates Sendai virus-induced apoptosis on mitochondri...	KEEP AS NON CORE	Summary: Supported in the antiviral MAVS/IRF3 literature, but this is a context-specific signaling role rather than TOMM70's core mitochondrial import function. Reason: Non-core signaling/adaptor role in antiviral innate immune response.
GO:0005742 mitochondrial outer membrane translocase complex	ISS GO_REF:0000024	ACCEPT	Summary: Correct complex annotation. TOMM70 associates with the TOM import machinery and acts as a receptor/adaptor at the outer membrane translocase.
GO:0008320 protein transmembrane transporter activity	ISS GO_REF:0000024	ACCEPT	Summary: Accepted as TOMM70 contribution to TOM-dependent protein transmembrane transport. TOMM70 is a receptor/adaptor, not the pore-forming subunit, but it contributes to the TOM complex import activity.
GO:0030150 protein import into mitochondrial matrix	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Broadly valid as a TOM-pathway outcome, but TOMM70 is best described as an outer-membrane receptor/adaptor rather than the matrix import pore or motor. Reason: Matrix import is one TOM-dependent route; TOMM70 has a more specific receptor/adaptor role for chaperone-bound precursors.
GO:0030943 mitochondrion targeting sequence binding	ISS GO_REF:0000024	ACCEPT	Summary: Supported. TOMM70 recognizes mitochondrial precursor proteins, especially hydrophobic internal-signal substrates delivered by Hsp70/Hsp90 chaperones.
GO:0045039 protein insertion into mitochondrial inner membrane	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Reasonable as a pathway-level consequence for carrier/internal-signal precursor delivery, but TOMM70 does not catalyze inner membrane insertion itself. Reason: TOMM70 acts upstream at the outer membrane before substrates are handed to downstream inner-membrane import machinery.
GO:0070585 protein localization to mitochondrion	ISS GO_REF:0000024	ACCEPT	Summary: Supported broad process annotation. TOMM70 promotes mitochondrial localization/import of precursor proteins through its receptor/adaptor role.
GO:0005515 protein binding	IPI PMID:23911537 Cytoplasmic ribosomal protein S3 (rpS3) plays a pivotal role...	REMOVE	Summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1 signaling. Reason: Replace generic protein binding curation with specific adaptor, receptor, TOM complex, and pathway annotations.
GO:0005739 mitochondrion	IDA PMID:20531390 Suppression of the novel ER protein Maxer by mutant ataxin-1...	MARK AS OVER ANNOTATED	Summary: Correct but too general. TOMM70 is specifically an outer mitochondrial membrane TOM receptor/adaptor. Reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
GO:0070062 extracellular exosome	HDA PMID:18570454 Proteomic analysis of exosomes from human neural stem cells ...	REMOVE	Summary: High-throughput extracellular exosome detection is not supported as TOMM70 functional localization and conflicts with the mitochondrial outer membrane synthesis. Reason: Likely high-throughput carryover/noise for an outer mitochondrial membrane TOM receptor.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MARK AS OVER ANNOTATED	Summary: Correct but too broad. The specific supported localization is mitochondrial outer membrane, not generic membrane. Reason: Subsumed by mitochondrial outer membrane annotations.
GO:0005742 mitochondrial outer membrane translocase complex	TAS PMID:15644312 Dissection of the mitochondrial import and assembly pathway ...	ACCEPT	Summary: Correct complex annotation. TOMM70 associates with the TOM import machinery and acts as a receptor/adaptor at the outer membrane translocase.
GO:0008320 protein transmembrane transporter activity	TAS PMID:15644312 Dissection of the mitochondrial import and assembly pathway ...	ACCEPT	Summary: Accepted as TOMM70 contribution to TOM-dependent protein transmembrane transport. TOMM70 is a receptor/adaptor, not the pore-forming subunit, but it contributes to the TOM complex import activity.
GO:0005515 protein binding	IPI PMID:12526792 Molecular chaperones Hsp90 and Hsp70 deliver preproteins to ...	MARK AS OVER ANNOTATED	Summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1 signaling. Reason: The interaction is documented, but generic protein binding should be superseded by specific adaptor, receptor, TOM complex, and pathway annotations.

Core Functions

TOMM70 is an outer-mitochondrial-membrane receptor/adaptor that docks Hsp70/Hsp90-bound hydrophobic precursor proteins and promotes their handoff to the TOM import machinery rather than acting as the pore itself.

Molecular Function:

protein-macromolecule adaptor activity

Directly Involved In:

protein localization to mitochondrion

Cellular Locations:

mitochondrial outer membrane

In Complex:

TOM complex

Supporting Evidence:

file:human/TOMM70/TOMM70-deep-research-falcon.md
TOMM70 is best understood as a **surface receptor/adaptor** of the **TOM (translocase of the outer membrane)** import gateway
file:human/TOMM70/TOMM70-deep-research-falcon.md
Cytosolic **Hsp70/Hsp90** chaperones bind newly synthesized hydrophobic precursors to prevent aggregation and **deliver them to TOMM70**
file:human/TOMM70/TOMM70-deep-research-falcon.md
TOMM70 is anchored in the **outer mitochondrial membrane (OMM)** with its receptor domain facing the cytosol.

References

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:12526792

Molecular chaperones Hsp90 and Hsp70 deliver preproteins to the mitochondrial import receptor Tom70.

PMID:15644312

Dissection of the mitochondrial import and assembly pathway for human Tom40.

PMID:18331822

Identification of Tom5 and Tom6 in the preprotein translocase complex of human mitochondrial outer membrane.

PMID:18570454

Proteomic analysis of exosomes from human neural stem cells by flow field-flow fractionation and nanoflow liquid chromatography-tandem mass spectrometry.

PMID:19946888

Defining the membrane proteome of NK cells.

PMID:20531390

Suppression of the novel ER protein Maxer by mutant ataxin-1 in Bergman glia contributes to non-cell-autonomous toxicity.

PMID:20628368

Tom70 mediates activation of interferon regulatory factor 3 on mitochondria.

PMID:23911537

Cytoplasmic ribosomal protein S3 (rpS3) plays a pivotal role in mitochondrial DNA damage surveillance.

PMID:25609812

Tom70 mediates Sendai virus-induced apoptosis on mitochondria.

PMID:32353859

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.

PMID:32728199

SARS-CoV-2 Orf9b suppresses type I interferon responses by targeting TOM70.

PMID:33060197

Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.

PMID:33723040

Toxoplasma gondii association with host mitochondria requires key mitochondrial protein import machinery.

PMID:33845483

Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV.

PMID:33990585

Crystal structure of SARS-CoV-2 Orf9b in complex with human TOM70 suggests unusual virus-host interactions.

PMID:34232536

Interactomes of SARS-CoV-2 and human coronaviruses reveal host factors potentially affecting pathogenesis.

PMID:34502139

Phosphorylation of SARS-CoV-2 Orf9b Regulates Its Targeting to Two Binding Sites in TOM70 and Recruitment of Hsp90.

PMID:34800366

Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.

PMID:34942634

Evolution of enhanced innate immune evasion by SARS-CoV-2.

PMID:35391620

The role of the individual TOM subunits in the association of PINK1 with depolarized mitochondria.

PMID:36217030

A comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets.

Reactome:R-HSA-5205661

Pink1 is recruited from the cytoplasm to the mitochondria

Reactome:R-HSA-9685281

SARS-CoV-1 3a binds TRAF3 within NLRP3 inflammasome

Reactome:R-HSA-9709663

SARS-CoV-2 9b binds TOMM70

Reactome:R-HSA-9709787

SARS-CoV-1 9b binds TOMM70

Reactome:R-HSA-9709842

MAVS binds TOMM70

Reactome:R-HSA-9709852

MAVS:TOMM70 recruits HSP90:TBK1:IRF3

file:human/TOMM70/TOMM70-deep-research-falcon.md

Falcon deep research report for human TOMM70

Suggested Experiments

Experiment: Compare import of carrier-type substrates and presequence substrates in TOMM70 knockout or knockdown cells rescued with wild-type versus chaperone-docking-defective TOMM70 variants.

Hypothesis: TOMM70 TPR-domain mutants that disrupt Hsp70/Hsp90 docking selectively impair carrier/internal-signal precursor import while preserving TOM core assembly.

Experiment: Assay MAVS-induced IRF3 activation and mitochondrial precursor import in parallel for TOMM70 interface mutants.

Hypothesis: TOMM70 antiviral signaling can be separated from its import receptor activity by mutating MAVS/Hsp90 signaling interfaces outside the precursor handoff surface.

Deep Research

Falcon

(TOMM70-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 29 citations 2026-05-11T13:44:11.524092

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Human TOMM70 (UniProt O94826) functional annotation

1) Target verification (gene/protein identity)

The literature retrieved and cited here matches the UniProt target O94826: human TOMM70 (synonyms TOM70, TOMM70A, KIAA0719) encoding mitochondrial import receptor subunit TOM70, a Tom70-family protein anchored in the outer mitochondrial membrane (OMM) with a large cytosolic receptor domain enriched in TPR (tetratricopeptide repeat) motifs. (kreimendahl2020themitochondrialouter pages 1-3, kreimendahl2020themitochondrialouter pages 3-6)

2) Key concepts, definitions, and current understanding

2.1 TOMM70 as a mitochondrial protein import receptor (core function)

Definition/role. TOMM70 is best understood as a surface receptor/adaptor of the TOM (translocase of the outer membrane) import gateway, specializing in the delivery of hydrophobic, chaperone-bound mitochondrial precursor proteins (classically including inner-membrane carrier proteins with internal targeting signals), rather than functioning as a channel itself. (kreimendahl2020themitochondrialouter pages 1-3, haastrup2023thejourneyof pages 8-10)

Mechanistic model. Cytosolic Hsp70/Hsp90 chaperones bind newly synthesized hydrophobic precursors to prevent aggregation and deliver them to TOMM70, which then hands off substrates to other TOM components (notably TOMM22 and the TOMM40 pore) for translocation across the OMM; carrier precursors are then escorted by small TIM chaperones in the IMS toward TIMM22 for insertion into the inner membrane. (haastrup2023thejourneyof pages 8-10, kreimendahl2020themitochondrialouter pages 12-14)

2.2 Domain architecture and chaperone docking

Tom70-family receptors are helical solenoids; a widely cited structural description (from fungal Tom70) is ~26 α-helices organized into ~11 TPR motifs, with an N-terminal membrane anchor and a cytosolic receptor domain. The N-terminal region forms a clamp-like site that binds Hsp70 (and in mammals Hsp70/Hsp90), supporting the view that TOMM70 frequently recognizes substrates indirectly via bound chaperones. (kreimendahl2020themitochondrialouter pages 3-6, kreimendahl2020themitochondrialouter pages 1-3)

2.3 Subcellular localization beyond “mitochondrial surface”: foci and contact sites

Beyond being OMM-anchored, TOMM70 is described as enriched in defined foci and associated with ER–mitochondria contact sites (MERCS) where it can contribute to Ca2+ transfer by interacting with IP3R3 (inositol-1,4,5-trisphosphate receptor type 3). This extends TOMM70’s annotation from import to organelle communication and signaling. (kreimendahl2020themitochondrialouter pages 14-16, pitt2021abiochemicaland pages 19-20)

2.4 TOMM70 as a signaling adaptor in innate immunity

TOMM70 is described as participating in antiviral innate immune signaling by acting as a receptor/scaffold for MAVS-associated signaling, helping recruit/organize signaling factors (often described via an Hsp90-containing axis) that promote IRF3 activation and type I interferon responses. (pitt2021abiochemicaland pages 19-20, pitt2021abiochemicaland pages 17-19)

2.5 TOMM70 in mitochondrial quality control and mitophagy

Multiple sources connect TOMM70 to PINK1/Parkin (PRKN)-dependent mitophagy, including roles in PINK1 import/accumulation at the OMM, TOM-complex ubiquitylation dynamics, and downstream mitophagy signaling. (kreimendahl2020themitochondrialouter pages 19-21, pitt2021abiochemicaland pages 17-19)

3) Recent developments (prioritizing 2023–2024)

3.1 2024: TOMM70 as a metabolic/immune node in human T cells (lactate → TOMM70 → MGAT1 import)

A 2024 Journal of Clinical Investigation study in human regulatory T cells (Tregs) proposed a direct metabolite–receptor interaction in which lactate binds TOM70 and promotes mitochondrial import of MGAT1, supporting OXPHOS and Treg function. The authors report (i) structural/docking and autoradiography evidence for lactate binding to TOM70, including predicted binding contacts (H-bonds with SER253, ASP541, THR511; hydrophobic contacts including PHE256, GLN255, ASN509, ALA510, CYS544), and (ii) functional perturbation where TOMM70 shRNA knockdown reduced MGAT1 expression/mitochondrial colocalization and decreased basal and maximal oxygen consumption rate (OCR). (zhou2024lactatesupportstreg pages 8-9)

Interpretation. This work extends TOMM70’s functional annotation into immunometabolism, framing TOMM70 not only as a protein import receptor but also as a potential “gatekeeper” for metabolically adaptive import programs in immune cells. (zhou2024lactatesupportstreg pages 8-9)

3.2 2024: Human genetic variation predicted to modulate TOMM70–SARS‑CoV‑2 ORF9b binding

A 2024 Scientific Reports computational study analyzed missense variants in TOMM70 at the TOMM70:ORF9b interface (structure referenced as PDB 7KDT) and predicted variant effects on binding affinity. Examples include predicted affinity increases (ΔΔG, kcal/mol) for V556L (0.905), K576R (0.618), A591T (0.599), V514I (0.562), and A483T (0.499), while I412T (−1.054) and E477G (−1.014) were predicted to decrease affinity. The same work reports these variants as rare in gnomAD, e.g., V556L observed with allele frequency 0.00007 in African/African American. (waman2024predictinghumanand pages 8-10)

Interpretation/limits. These are in silico affinity predictions rather than clinical association estimates; nonetheless they provide a concrete hypothesis framework for host genetic modulation of viral immune evasion mediated via TOMM70. (waman2024predictinghumanand pages 8-10)

3.3 2023–2024: TOMM70 highlighted as a multifunctional/regulatory TOM component

A 2023 review on mitochondrial import-related stress signaling summarizes the import machinery as a signaling hub; it notes that Tom20 and Tom70 are the main receptors and links TOM-associated processes to mitophagy and stress responses (e.g., PINK1-related pathways when import is perturbed). (lionaki2023mitochondrialproteinimport pages 8-9)

A 2024 evolutionary/functional review specifically emphasizes TOMM70 as a TOM receptor with “manifold functions” and places it in the context of evolutionary diversification of TOM composition and regulation, aligning TOMM70 with regulatory and signaling roles beyond translocation. (ozdemir2024thetomcomplex pages 1-7)

4) Current applications and real-world implementations

4.1 Diagnostic relevance: TOMM70 as a Mendelian mitochondrial disease gene

A 2020 human genetics study reports compound heterozygous TOMM70 variants (c.794C>T / p.T265M and c.1745C>T / p.A582V) in a patient with severe anemia, lactic acidosis, and developmental delay, with patient-derived lymphocytes showing reduced TOM70 expression and defects in TOM complexes and multi-OXPHOS, with complex IV primarily affected; WT TOM70 (but not mutant TOM70) restored the complex IV defect in a knockdown rescue model. This supports clinical use of TOMM70 in gene panels/interpretation for suspected mitochondrial disease. (wei2020mutationsintomm70 pages 1-2)

4.2 Therapeutic strategy concepts (preclinical): modulating TOMM70-linked pathways

TOMM70’s central placement at the intersection of protein import, MERCS, and innate immunity has motivated proposals that targeting TOM-complex interfaces or TOMM70-linked signaling could be therapeutically relevant in contexts such as viral immune evasion and mitochondrial-stress diseases. A structural/biochemical review highlights TOMM70’s involvement in Parkin/PINK1 mitophagy and MAVS–IRF3 signaling and notes viral exploitation (e.g., ORF9b binding) as a rationale for intervention concepts. (pitt2021abiochemicaland pages 19-20, pitt2021abiochemicaland pages 17-19)

4.3 Cell therapy context (Treg function)

The 2024 JCI study connects TOMM70-dependent MGAT1 mitochondrial localization to improved human Treg OXPHOS and reports in vivo benefit of lactate-treated Tregs in a xenogeneic GvHD model, positioning TOMM70 mechanistically within workflows relevant to Treg reinfusion therapy (as an enabling step for mitochondrial metabolic fitness). (zhou2024lactatesupportstreg pages 8-9)

5) Expert opinions and authoritative synthesis (how experts frame TOMM70)

Consensus functional framing. Authoritative reviews converge on TOMM70 as a TPR-containing OMM adaptor receptor that (i) docks Hsp70/Hsp90-bound precursors to the TOM entry gate, (ii) coordinates organelle cross-talk (MERCS; Ca2+ transfer via IP3R3), and (iii) provides a platform for innate immune signaling (MAVS/IRF3 axis) and quality control (PINK1/Parkin mitophagy). (kreimendahl2020themitochondrialouter pages 1-3, pitt2021abiochemicaland pages 19-20)

Mechanistic caution expressed in the literature. The same reviews highlight that substrate recognition can be predominantly chaperone-mediated, and that TOMM70’s “non-import” roles likely depend on context-specific protein–protein interactions and post-translational modifications (phosphorylation/ubiquitylation), with open questions about how these modifications reprogram TOMM70’s receptor vs signaling functions in mammals. (kreimendahl2020themitochondrialouter pages 3-6, pitt2021abiochemicaland pages 17-19)

6) Quantitative/statistical findings from recent and key studies

6.1 Structural/domain quantitative descriptors

A commonly cited Tom70 structural summary is ~26 α-helices forming ~11 TPR motifs in the receptor domain. (kreimendahl2020themitochondrialouter pages 3-6)

6.2 Import-system scale

Reviews estimate that human cells import on the order of ~1,500 mitochondrial precursor proteins synthesized in the cytosol, contextualizing why TOM receptors (including TOMM70) are essential for cell viability and homeostasis. (kreimendahl2020themitochondrialouter pages 1-3)

6.3 Quantitative variant effects and population frequencies relevant to TOMM70–ORF9b interaction (2024)

Predicted changes in binding affinity to SARS‑CoV‑2 ORF9b for TOMM70 variants include V556L ΔΔG 0.905 kcal/mol, K576R 0.618, A591T 0.599, V514I 0.562, A483T 0.499, and affinity-reducing I412T −1.054 and E477G −1.014. Reported allele frequencies are far below 1% (e.g., V556L 0.00007 in African/African American). (waman2024predictinghumanand pages 8-10)

6.4 Quantitative/statistical evidence in the 2024 Treg study

The 2024 JCI study reports statistical testing (e.g., ANOVA with P-value thresholds) for multiple mitochondrial readouts and shows that TOMM70 knockdown reduces mitochondrial MGAT1 colocalization and OCR; however, the excerpted text does not provide the exact OCR deltas, so quantitative effect sizes cannot be faithfully reproduced here without the underlying supplemental figure values. (zhou2024lactatesupportstreg pages 8-9)

7) Visual evidence (figures) supporting mechanistic understanding

A Tom70 review provides schematics that summarize: (i) Tom70’s receptor function as a docking site for chaperone-bound substrates and their delivery to the TOM pore and/or outer-membrane insertion pathways, (ii) Tom70’s role in MAVS/RIG-I pathway signaling through recruitment of Hsp90/TBK1/IRF3 complexes, and (iii) competitive binding of SARS‑CoV‑2 ORF9b to Tom70 that can suppress interferon responses. These schematics are useful for functional annotation narratives. (kreimendahl2020themitochondrialouter media bc2f2392, kreimendahl2020themitochondrialouter media 1214cc5a, kreimendahl2020themitochondrialouter media 41a8d14b, kreimendahl2020themitochondrialouter media 44199fa5, kreimendahl2020themitochondrialouter media 3b13eb9e)

8) Summary functional annotation (most defensible “primary function”)

Primary function: TOMM70 is an outer-mitochondrial-membrane receptor/adaptor that binds cytosolic chaperones (Hsp70/Hsp90) carrying hydrophobic mitochondrial precursor proteins and promotes their delivery to the TOM translocation machinery for import—particularly important for internal-signal, hydrophobic precursors such as carrier proteins. (haastrup2023thejourneyof pages 8-10, kreimendahl2020themitochondrialouter pages 12-14)

Where it acts: OMM, cytosol-facing receptor domain; additionally enriched at MERCS where it can participate in ER→mitochondria Ca2+ transfer and signaling assemblies. (kreimendahl2020themitochondrialouter pages 14-16, pitt2021abiochemicaland pages 19-20)

Key pathways: Mitochondrial biogenesis (protein import), innate immune signaling (MAVS/IRF3 axis, viral antagonism via ORF9b), and mitochondrial quality control/mitophagy (PINK1/Parkin-linked processes). (pitt2021abiochemicaland pages 19-20, kreimendahl2020themitochondrialouter pages 19-21)

Evidence-mapped reference table

The following table consolidates identity, mechanism, pathways, 2023–2024 updates, quantitative findings, and URLs.

Category	Specific details	Evidence/notes	Key sources with publication year	URL	Citation context IDs
Identity/domains	Human TOMM70 corresponds to UniProt O94826 and encodes the mitochondrial outer membrane import receptor Tom70/TOM70/TOMM70A. It is a Tom70-family protein with an N-terminal membrane anchor and a large cytosolic TPR-repeat receptor domain; reviews describe Tom70 as a helical receptor with ~26 α-helices and ~11 TPR motifs.	Identity and function match the UniProt target, and the TPR-repeat architecture aligns with the provided InterPro/Pfam annotations. Evolutionary review notes strong conservation among animal orthologs.	Kreimendahl & Rassow 2020; Özdemir & Dennerlein 2024	https://doi.org/10.3390/ijms21197262 ; https://doi.org/10.1515/hsz-2024-0043	(kreimendahl2020themitochondrialouter pages 1-3, kreimendahl2020themitochondrialouter pages 3-6, ozdemir2024thetomcomplex pages 1-7)
Localization	TOMM70 is anchored in the outer mitochondrial membrane (OMM) with its receptor domain facing the cytosol. In mammalian cells it is also enriched in defined foci and at ER-mitochondria contact sites (MERCS).	Reviews describe localization on the mitochondrial surface and clustering at contact sites, consistent with roles in import, Ca2+ transfer, and signaling.	Kreimendahl & Rassow 2020; Pitt & Buchanan 2021	https://doi.org/10.3390/ijms21197262 ; https://doi.org/10.3390/cells10051164	(kreimendahl2020themitochondrialouter pages 1-3, kreimendahl2020themitochondrialouter pages 14-16, pitt2021abiochemicaland pages 19-20, kreimendahl2020themitochondrialouter pages 12-14)
Core function in import	TOMM70 is a surface receptor for chaperone-bound hydrophobic mitochondrial precursor proteins, especially multi-pass carrier proteins with internal targeting signals. Cytosolic Hsp70/Hsp90 chaperones deliver precursors to TOMM70, which then transfers them to TOMM22/TOMM40 for passage through the TOM pore and onward to TIM22 for inner-membrane carrier insertion.	This is the best-supported primary annotation: TOMM70 acts mainly as an adaptor/docking receptor rather than as a pore-forming transporter or enzyme. TOMM20 is emphasized as the main receptor for classical N-terminal presequences, whereas TOMM70 is more associated with carrier/internal-signal substrates.	Haastrup et al. 2023; Kreimendahl & Rassow 2020; Lionaki et al. 2023	https://doi.org/10.3390/ijms24032479 ; https://doi.org/10.3390/ijms21197262 ; https://doi.org/10.1002/bies.202200160	(haastrup2023thejourneyof pages 8-10, kreimendahl2020themitochondrialouter pages 1-3, kreimendahl2020themitochondrialouter pages 12-14, lionaki2023mitochondrialproteinimport pages 8-9)
Key interactions	Established interactors include Hsp70/Hsp90, TOMM20/TOMM22/TOMM40, PINK1, Parkin/PRKN, MAVS, and IP3R3; mammalian studies also link TOMM70 to IRF3/TBK1 signaling complexes via Hsp90 and to viral proteins including SARS-CoV-2 ORF9b.	N-terminal TPR motifs mediate chaperone docking; TOMM70 can partially/reversibly associate with the TOM core. Beyond import, it serves as a scaffold for antiviral signaling and membrane-contact functions.	Kreimendahl & Rassow 2020; Pitt & Buchanan 2021	https://doi.org/10.3390/ijms21197262 ; https://doi.org/10.3390/cells10051164	(kreimendahl2020themitochondrialouter pages 1-3, kreimendahl2020themitochondrialouter pages 14-16, pitt2021abiochemicaland pages 19-20, kreimendahl2020themitochondrialouter pages 12-14, pitt2021abiochemicaland pages 17-19)
Pathways	Major pathways include mitochondrial protein import, PINK1/Parkin-dependent mitophagy, MAVS-mediated innate antiviral signaling, and ER-mitochondria Ca2+ transfer/MERCS.	Reviews and mechanistic papers place TOMM70 at the intersection of organelle biogenesis and stress signaling: import defects can alter cytosolic proteostasis, ISR/UPR-like pathways, and mitophagy initiation.	Lionaki et al. 2023; Kreimendahl & Rassow 2020; Pitt & Buchanan 2021	https://doi.org/10.1002/bies.202200160 ; https://doi.org/10.3390/ijms21197262 ; https://doi.org/10.3390/cells10051164	(lionaki2023mitochondrialproteinimport pages 8-9, kreimendahl2020themitochondrialouter pages 19-21, pitt2021abiochemicaland pages 19-20)
Disease/clinical relevance	Pathogenic TOMM70 variants cause a rare mitochondrial disease with multi-OXPHOS deficiency, severe anemia, lactic acidosis, and developmental delay. Reported patient variants include p.T265M and p.A582V. TOMM70 dysregulation is also discussed in cardiac injury/remodeling, neurodegeneration/mitophagy, and antiviral immune evasion.	Patient-derived lymphocytes showed reduced TOM70 expression and TOM complex defects; only wild-type TOM70 restored defects in rescue assays. Reviews link reduced TOM70 to impaired mitochondrial quality control and stress susceptibility.	Wei et al. 2020; Palmer et al. 2021; Kreimendahl & Rassow 2020	https://doi.org/10.1038/s10038-019-0714-1 ; https://doi.org/10.1002/1873-3468.14022 ; https://doi.org/10.3390/ijms21197262	(wei2020mutationsintomm70 pages 1-2, kreimendahl2020themitochondrialouter pages 19-21)
2023-2024 updates	2024 JCI: lactate was shown to bind TOM70 and promote MGAT1-TOM70 interaction and mitochondrial translocation of MGAT1 in human Tregs, supporting OXPHOS and Treg function. 2024 Sci Rep: human TOMM70 missense variants were computationally predicted to alter binding to SARS-CoV-2 ORF9b. 2024 review: TOMM70 highlighted as an evolutionarily flexible TOM component with signaling and contact-site functions beyond import.	These recent papers expand TOMM70 biology from import receptor to broader signaling node in immune metabolism and host-virus interaction. The 2024 review emphasizes TOMM70 as a regulatory, non-core-pore TOM component with manifold functions.	Zhou et al. 2024; Waman et al. 2024; Özdemir & Dennerlein 2024	https://doi.org/10.1172/jci175897 ; https://doi.org/10.1038/s41598-024-61541-1 ; https://doi.org/10.1515/hsz-2024-0043	(zhou2024lactatesupportstreg pages 8-9, waman2024predictinghumanand pages 8-10, ozdemir2024thetomcomplex pages 1-7)
Quantitative/statistical data	Recent quantitative details include: ~26 α-helices / ~11 TPR motifs for Tom70 architecture; human mitochondrial proteome estimate of up to ~1,500 proteins requiring import; lactate-TOM70 docking implicated residues SER253, ASP541, THR511, PHE256, GLN255, ASN509, ALA510, CYS544; predicted TOMM70 variant effects on ORF9b binding include V556L ΔΔG 0.905 kcal/mol, K576R 0.618, A591T 0.599, V514I 0.562, A483T 0.499, while I412T -1.054 and E477G -1.014 kcal/mol were predicted to reduce affinity; the reported mitochondrial disease prevalence background cited is 5-15 per 100,000 live births.	Quantitative figures are heterogeneous: some are structural descriptors, some are computational affinity estimates, and some are disease epidemiology/background. Several functional studies reported significant changes (e.g., OCR decline after TOMM70 knockdown) but the excerpted text did not provide exact numeric effect sizes. Rare TOMM70 affinity-enhancing variants had gnomAD frequencies far below 1% (e.g., V556L African/AA 0.00007).	Kreimendahl & Rassow 2020; Zhou et al. 2024; Waman et al. 2024; Wei et al. 2020	https://doi.org/10.3390/ijms21197262 ; https://doi.org/10.1172/jci175897 ; https://doi.org/10.1038/s41598-024-61541-1 ; https://doi.org/10.1038/s10038-019-0714-1	(kreimendahl2020themitochondrialouter pages 1-3, kreimendahl2020themitochondrialouter pages 3-6, zhou2024lactatesupportstreg pages 8-9, waman2024predictinghumanand pages 8-10, wei2020mutationsintomm70 pages 1-2)

Table: This table summarizes the verified identity, localization, core function, interactions, pathways, disease relevance, recent 2023-2024 advances, and available quantitative findings for human TOMM70 (UniProt O94826). It is designed as a compact evidence map for functional annotation and literature-supported reporting.

Key cited sources (publication date; URL)

Kreimendahl S, Rassow J. Int J Mol Sci 2020-10. https://doi.org/10.3390/ijms21197262 (kreimendahl2020themitochondrialouter pages 1-3)
Wei X et al. Journal of Human Genetics 2020-01 (accepted 2019-12-15). https://doi.org/10.1038/s10038-019-0714-1 (wei2020mutationsintomm70 pages 1-2)
Pitt AS, Buchanan SK. Cells 2021-05. https://doi.org/10.3390/cells10051164 (pitt2021abiochemicaland pages 19-20)
Haastrup MO et al. Int J Mol Sci 2023-01. https://doi.org/10.3390/ijms24032479 (haastrup2023thejourneyof pages 8-10)
Lionaki E et al. BioEssays 2023-01. https://doi.org/10.1002/bies.202200160 (lionaki2023mitochondrialproteinimport pages 8-9)
Zhou J et al. J Clin Invest 2024-09. https://doi.org/10.1172/jci175897 (zhou2024lactatesupportstreg pages 8-9)
Özdemir M, Dennerlein S. Biological Chemistry 2024-08. https://doi.org/10.1515/hsz-2024-0043 (ozdemir2024thetomcomplex pages 1-7)
Waman VP et al. Scientific Reports 2024-11. https://doi.org/10.1038/s41598-024-61541-1 (waman2024predictinghumanand pages 8-10)

References

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(zhou2024lactatesupportstreg pages 8-9): Jinren Zhou, Jian Gu, Qufei Qian, Yigang Zhang, Tianning Huang, Xiangyu Li, Zhuoqun Liu, Qing Shao, Yuan Liang, Lei Qiao, Xiaozhang Xu, Qiuyang Chen, Zibo Xu, Yu Li, Ji Gao, Yufeng Pan, Yiming Wang, Roderick O’Connor, Keli L. Hippen, Ling Lu, and Bruce R. Blazar. Lactate supports treg function and immune balance via mgat1 effects on n-glycosylation in the mitochondria. Journal of Clinical Investigation, Sep 2024. URL: https://doi.org/10.1172/jci175897, doi:10.1172/jci175897. This article has 48 citations and is from a highest quality peer-reviewed journal.
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(kreimendahl2020themitochondrialouter media 1214cc5a): Sebastian Kreimendahl and Joachim Rassow. The mitochondrial outer membrane protein tom70-mediator in protein traffic, membrane contact sites and innate immunity. International Journal of Molecular Sciences, 21:7262, Oct 2020. URL: https://doi.org/10.3390/ijms21197262, doi:10.3390/ijms21197262. This article has 98 citations.
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Citations

zhou2024lactatesupportstreg pages 8-9
waman2024predictinghumanand pages 8-10
lionaki2023mitochondrialproteinimport pages 8-9
ozdemir2024thetomcomplex pages 1-7
kreimendahl2020themitochondrialouter pages 3-6
kreimendahl2020themitochondrialouter pages 1-3
pitt2021abiochemicaland pages 19-20
haastrup2023thejourneyof pages 8-10
kreimendahl2020themitochondrialouter pages 12-14
kreimendahl2020themitochondrialouter pages 14-16
pitt2021abiochemicaland pages 17-19
kreimendahl2020themitochondrialouter pages 19-21
https://doi.org/10.3390/ijms21197262
https://doi.org/10.1515/hsz-2024-0043
https://doi.org/10.3390/cells10051164
https://doi.org/10.3390/ijms24032479
https://doi.org/10.1002/bies.202200160
https://doi.org/10.1038/s10038-019-0714-1
https://doi.org/10.1002/1873-3468.14022
https://doi.org/10.1172/jci175897
https://doi.org/10.1038/s41598-024-61541-1
https://doi.org/10.3390/ijms21197262,
https://doi.org/10.3390/ijms24032479,
https://doi.org/10.3390/cells10051164,
https://doi.org/10.1172/jci175897,
https://doi.org/10.1038/s41598-024-61541-1,
https://doi.org/10.1002/bies.202200160,
https://doi.org/10.1515/hsz-2024-0043,
https://doi.org/10.1038/s10038-019-0714-1,

📄 View Raw YAML

id: O94826
gene_symbol: TOMM70
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: TOMM70 is a cytosol-facing mitochondrial outer membrane TOM receptor/adaptor.
  Its primary role is to dock Hsp70/Hsp90-bound hydrophobic mitochondrial precursor proteins,
  especially internal-signal/carrier-type substrates, and deliver them to the TOM translocation
  machinery. It also has supported non-core signaling roles in MAVS/IRF3 antiviral responses
  and PINK1/Parkin-linked mitochondrial quality control.
existing_annotations:
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor
      with a cytosol-facing TPR receptor domain.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TOMM70/TOMM70-deep-research-falcon.md
      supporting_text: TOMM70 is anchored in the **outer mitochondrial membrane (OMM)** with
        its receptor domain facing the cytosol.
- term:
    id: GO:0008320
    label: protein transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: Accepted as TOMM70 contribution to TOM-dependent protein transmembrane transport.
      TOMM70 is a receptor/adaptor, not the pore-forming subunit, but it contributes to the
      TOM complex import activity.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TOMM70/TOMM70-deep-research-falcon.md
      supporting_text: TOMM70 is best understood as a **surface receptor/adaptor** of the
        **TOM (translocase of the outer membrane)** import gateway
- term:
    id: GO:0030150
    label: protein import into mitochondrial matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Broadly valid as a TOM-pathway outcome, but TOMM70 is best described as an outer-membrane
      receptor/adaptor rather than the matrix import pore or motor.
    action: KEEP_AS_NON_CORE
    reason: Matrix import is one TOM-dependent route; TOMM70 has a more specific receptor/adaptor
      role for chaperone-bound precursors.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0030943
    label: mitochondrion targeting sequence binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Supported. TOMM70 recognizes mitochondrial precursor proteins, especially hydrophobic
      internal-signal substrates delivered by Hsp70/Hsp90 chaperones.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TOMM70/TOMM70-deep-research-falcon.md
      supporting_text: Cytosolic **Hsp70/Hsp90** chaperones bind newly synthesized hydrophobic
        precursors to prevent aggregation and **deliver them to TOMM70**
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Reasonable as a pathway-level consequence for carrier/internal-signal precursor
      delivery, but TOMM70 does not catalyze inner membrane insertion itself.
    action: KEEP_AS_NON_CORE
    reason: TOMM70 acts upstream at the outer membrane before substrates are handed to downstream
      inner-membrane import machinery.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor
      with a cytosol-facing TPR receptor domain.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32353859
  review:
    summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound
      precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1
      signaling.
    action: REMOVE
    reason: Replace generic protein binding curation with specific adaptor, receptor, TOM
      complex, and pathway annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32728199
  review:
    summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound
      precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1
      signaling.
    action: REMOVE
    reason: Replace generic protein binding curation with specific adaptor, receptor, TOM
      complex, and pathway annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33060197
  review:
    summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound
      precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1
      signaling.
    action: REMOVE
    reason: Replace generic protein binding curation with specific adaptor, receptor, TOM
      complex, and pathway annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33845483
  review:
    summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound
      precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1
      signaling.
    action: REMOVE
    reason: Replace generic protein binding curation with specific adaptor, receptor, TOM
      complex, and pathway annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33990585
  review:
    summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound
      precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1
      signaling.
    action: MARK_AS_OVER_ANNOTATED
    reason: The interaction is documented, but generic protein binding should be superseded
      by specific adaptor, receptor, TOM complex, and pathway annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34232536
  review:
    summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound
      precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1
      signaling.
    action: REMOVE
    reason: Replace generic protein binding curation with specific adaptor, receptor, TOM
      complex, and pathway annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34502139
  review:
    summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound
      precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1
      signaling.
    action: REMOVE
    reason: Replace generic protein binding curation with specific adaptor, receptor, TOM
      complex, and pathway annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34942634
  review:
    summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound
      precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1
      signaling.
    action: REMOVE
    reason: Replace generic protein binding curation with specific adaptor, receptor, TOM
      complex, and pathway annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36217030
  review:
    summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound
      precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1
      signaling.
    action: REMOVE
    reason: Replace generic protein binding curation with specific adaptor, receptor, TOM
      complex, and pathway annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Correct but too general. TOMM70 is specifically an outer mitochondrial membrane
      TOM receptor/adaptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0030150
    label: protein import into mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Broadly valid as a TOM-pathway outcome, but TOMM70 is best described as an outer-membrane
      receptor/adaptor rather than the matrix import pore or motor.
    action: KEEP_AS_NON_CORE
    reason: Matrix import is one TOM-dependent route; TOMM70 has a more specific receptor/adaptor
      role for chaperone-bound precursors.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0061052
    label: negative regulation of cell growth involved in cardiac muscle cell development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Automatic orthology transfer is not supported by the TOMM70 literature synthesis
      as a direct function of this gene product.
    action: REMOVE
    reason: Developmental/thyroxine response terms overreach beyond TOMM70's demonstrated
      receptor/adaptor and signaling roles.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0097068
    label: response to thyroxine
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Automatic orthology transfer is not supported by the TOMM70 literature synthesis
      as a direct function of this gene product.
    action: REMOVE
    reason: Developmental/thyroxine response terms overreach beyond TOMM70's demonstrated
      receptor/adaptor and signaling roles.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:1903749
    label: positive regulation of protein localization to mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Supported broad process annotation. TOMM70 promotes mitochondrial localization/import
      of precursor proteins through its receptor/adaptor role.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Correct but too general. TOMM70 is specifically an outer mitochondrial membrane
      TOM receptor/adaptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0030150
    label: protein import into mitochondrial matrix
  evidence_type: TAS
  original_reference_id: PMID:15644312
  review:
    summary: Broadly valid as a TOM-pathway outcome, but TOMM70 is best described as an outer-membrane
      receptor/adaptor rather than the matrix import pore or motor.
    action: KEEP_AS_NON_CORE
    reason: Matrix import is one TOM-dependent route; TOMM70 has a more specific receptor/adaptor
      role for chaperone-bound precursors.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: NAS
  original_reference_id: PMID:18331822
  review:
    summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor
      with a cytosol-facing TPR receptor domain.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0045040
    label: protein insertion into mitochondrial outer membrane
  evidence_type: NAS
  original_reference_id: PMID:18331822
  review:
    summary: The annotation captures mitochondrial protein import context but overstates TOMM70
      as an outer-membrane insertase.
    action: MODIFY
    reason: TOMM70 is a receptor/adaptor for precursor targeting/import, not the SAM/outer-membrane
      insertion machinery.
    proposed_replacement_terms:
    - id: GO:0070585
      label: protein localization to mitochondrion
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0140596
    label: TOM complex
  evidence_type: NAS
  original_reference_id: PMID:18331822
  review:
    summary: Correct and specific. TOMM70 is a TOM-complex receptor component rather than
      an independent pore-forming subunit.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: EXP
  original_reference_id: PMID:20628368
  review:
    summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor
      with a cytosol-facing TPR receptor domain.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: EXP
  original_reference_id: PMID:25609812
  review:
    summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor
      with a cytosol-facing TPR receptor domain.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: EXP
  original_reference_id: PMID:33723040
  review:
    summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor
      with a cytosol-facing TPR receptor domain.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  review:
    summary: Correct but too general. TOMM70 is specifically an outer mitochondrial membrane
      TOM receptor/adaptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35391620
  review:
    summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound
      precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1
      signaling.
    action: MARK_AS_OVER_ANNOTATED
    reason: The interaction is documented, but generic protein binding should be superseded
      by specific adaptor, receptor, TOM complex, and pathway annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:20628368
  review:
    summary: Accepted. TOMM70 functions as a receptor/adaptor for chaperone-bound mitochondrial
      precursor proteins and also as a MAVS-linked signaling scaffold.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TOMM70/TOMM70-deep-research-falcon.md
      supporting_text: TOMM70 is best understood as a **surface receptor/adaptor** of the
        **TOM (translocase of the outer membrane)** import gateway
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IDA
  original_reference_id: PMID:20628368
  review:
    summary: Correct but too broad. The specific supported localization is mitochondrial outer
      membrane, not generic mitochondrial membrane.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by mitochondrial outer membrane annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5205661
  review:
    summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor
      with a cytosol-facing TPR receptor domain.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9685281
  review:
    summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor
      with a cytosol-facing TPR receptor domain.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9709663
  review:
    summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor
      with a cytosol-facing TPR receptor domain.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9709787
  review:
    summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor
      with a cytosol-facing TPR receptor domain.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9709842
  review:
    summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor
      with a cytosol-facing TPR receptor domain.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9709852
  review:
    summary: Correct localization. TOMM70 is an outer mitochondrial membrane TOM receptor/adaptor
      with a cytosol-facing TPR receptor domain.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0002218
    label: activation of innate immune response
  evidence_type: IDA
  original_reference_id: PMID:20628368
  review:
    summary: Supported in the antiviral MAVS/IRF3 literature, but this is a context-specific
      signaling role rather than TOMM70's core mitochondrial import function.
    action: KEEP_AS_NON_CORE
    reason: Non-core signaling/adaptor role in antiviral innate immune response.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0002230
    label: positive regulation of defense response to virus by host
  evidence_type: IDA
  original_reference_id: PMID:20628368
  review:
    summary: Supported in the antiviral MAVS/IRF3 literature, but this is a context-specific
      signaling role rather than TOMM70's core mitochondrial import function.
    action: KEEP_AS_NON_CORE
    reason: Non-core signaling/adaptor role in antiviral innate immune response.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20628368
  review:
    summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound
      precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1
      signaling.
    action: REMOVE
    reason: Replace generic protein binding curation with specific adaptor, receptor, TOM
      complex, and pathway annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25609812
  review:
    summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound
      precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1
      signaling.
    action: REMOVE
    reason: Replace generic protein binding curation with specific adaptor, receptor, TOM
      complex, and pathway annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:20628368
  review:
    summary: Correct but too general. TOMM70 is specifically an outer mitochondrial membrane
      TOM receptor/adaptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:25609812
  review:
    summary: Correct but too general. TOMM70 is specifically an outer mitochondrial membrane
      TOM receptor/adaptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0032728
    label: positive regulation of interferon-beta production
  evidence_type: IDA
  original_reference_id: PMID:20628368
  review:
    summary: Supported in the antiviral MAVS/IRF3 literature, but this is a context-specific
      signaling role rather than TOMM70's core mitochondrial import function.
    action: KEEP_AS_NON_CORE
    reason: Non-core signaling/adaptor role in antiviral innate immune response.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TOMM70/TOMM70-deep-research-falcon.md
      supporting_text: TOMM70 is described as participating in antiviral innate immune signaling
        by acting as a **receptor/scaffold for MAVS-associated signaling**
- term:
    id: GO:0042981
    label: regulation of apoptotic process
  evidence_type: IDA
  original_reference_id: PMID:25609812
  review:
    summary: Supported for Sendai virus-induced TOMM70/Hsp90/IRF3/BAX apoptosis context, but
      it is a secondary signaling phenotype.
    action: KEEP_AS_NON_CORE
    reason: Context-specific antiviral/apoptosis role rather than primary mitochondrial import
      function.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0098586
    label: cellular response to virus
  evidence_type: IDA
  original_reference_id: PMID:25609812
  review:
    summary: Supported in the antiviral MAVS/IRF3 literature, but this is a context-specific
      signaling role rather than TOMM70's core mitochondrial import function.
    action: KEEP_AS_NON_CORE
    reason: Non-core signaling/adaptor role in antiviral innate immune response.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005742
    label: mitochondrial outer membrane translocase complex
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Correct complex annotation. TOMM70 associates with the TOM import machinery and
      acts as a receptor/adaptor at the outer membrane translocase.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0008320
    label: protein transmembrane transporter activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: contributes_to
  review:
    summary: Accepted as TOMM70 contribution to TOM-dependent protein transmembrane transport.
      TOMM70 is a receptor/adaptor, not the pore-forming subunit, but it contributes to the
      TOM complex import activity.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0030150
    label: protein import into mitochondrial matrix
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Broadly valid as a TOM-pathway outcome, but TOMM70 is best described as an outer-membrane
      receptor/adaptor rather than the matrix import pore or motor.
    action: KEEP_AS_NON_CORE
    reason: Matrix import is one TOM-dependent route; TOMM70 has a more specific receptor/adaptor
      role for chaperone-bound precursors.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0030943
    label: mitochondrion targeting sequence binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Supported. TOMM70 recognizes mitochondrial precursor proteins, especially hydrophobic
      internal-signal substrates delivered by Hsp70/Hsp90 chaperones.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0045039
    label: protein insertion into mitochondrial inner membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Reasonable as a pathway-level consequence for carrier/internal-signal precursor
      delivery, but TOMM70 does not catalyze inner membrane insertion itself.
    action: KEEP_AS_NON_CORE
    reason: TOMM70 acts upstream at the outer membrane before substrates are handed to downstream
      inner-membrane import machinery.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0070585
    label: protein localization to mitochondrion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Supported broad process annotation. TOMM70 promotes mitochondrial localization/import
      of precursor proteins through its receptor/adaptor role.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23911537
  review:
    summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound
      precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1
      signaling.
    action: REMOVE
    reason: Replace generic protein binding curation with specific adaptor, receptor, TOM
      complex, and pathway annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:20531390
  review:
    summary: Correct but too general. TOMM70 is specifically an outer mitochondrial membrane
      TOM receptor/adaptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:18570454
  review:
    summary: High-throughput extracellular exosome detection is not supported as TOMM70 functional
      localization and conflicts with the mitochondrial outer membrane synthesis.
    action: REMOVE
    reason: Likely high-throughput carryover/noise for an outer mitochondrial membrane TOM
      receptor.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  review:
    summary: Correct but too broad. The specific supported localization is mitochondrial outer
      membrane, not generic membrane.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by mitochondrial outer membrane annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005742
    label: mitochondrial outer membrane translocase complex
  evidence_type: TAS
  original_reference_id: PMID:15644312
  review:
    summary: Correct complex annotation. TOMM70 associates with the TOM import machinery and
      acts as a receptor/adaptor at the outer membrane translocase.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0008320
    label: protein transmembrane transporter activity
  evidence_type: TAS
  original_reference_id: PMID:15644312
  review:
    summary: Accepted as TOMM70 contribution to TOM-dependent protein transmembrane transport.
      TOMM70 is a receptor/adaptor, not the pore-forming subunit, but it contributes to the
      TOM complex import activity.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12526792
  review:
    summary: Protein binding is too generic for TOMM70. The informative functions are chaperone-bound
      precursor receptor/adaptor activity, TOM association, and context-specific MAVS/PINK1
      signaling.
    action: MARK_AS_OVER_ANNOTATED
    reason: The interaction is documented, but generic protein binding should be superseded
      by specific adaptor, receptor, TOM complex, and pathway annotations.
    additional_reference_ids:
    - file:human/TOMM70/TOMM70-deep-research-falcon.md
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs
    using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12526792
  title: Molecular chaperones Hsp90 and Hsp70 deliver preproteins to the mitochondrial import
    receptor Tom70.
  findings: []
- id: PMID:15644312
  title: Dissection of the mitochondrial import and assembly pathway for human Tom40.
  findings: []
- id: PMID:18331822
  title: Identification of Tom5 and Tom6 in the preprotein translocase complex of human mitochondrial
    outer membrane.
  findings: []
- id: PMID:18570454
  title: Proteomic analysis of exosomes from human neural stem cells by flow field-flow fractionation
    and nanoflow liquid chromatography-tandem mass spectrometry.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20531390
  title: Suppression of the novel ER protein Maxer by mutant ataxin-1 in Bergman glia contributes
    to non-cell-autonomous toxicity.
  findings: []
- id: PMID:20628368
  title: Tom70 mediates activation of interferon regulatory factor 3 on mitochondria.
  findings: []
- id: PMID:23911537
  title: Cytoplasmic ribosomal protein S3 (rpS3) plays a pivotal role in mitochondrial DNA
    damage surveillance.
  findings: []
- id: PMID:25609812
  title: Tom70 mediates Sendai virus-induced apoptosis on mitochondria.
  findings: []
- id: PMID:32353859
  title: A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.
  findings: []
- id: PMID:32728199
  title: SARS-CoV-2 Orf9b suppresses type I interferon responses by targeting TOM70.
  findings: []
- id: PMID:33060197
  title: Comparative host-coronavirus protein interaction networks reveal pan-viral disease
    mechanisms.
  findings: []
- id: PMID:33723040
  title: Toxoplasma gondii association with host mitochondria requires key mitochondrial protein
    import machinery.
  findings: []
- id: PMID:33845483
  title: Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV.
  findings: []
- id: PMID:33990585
  title: Crystal structure of SARS-CoV-2 Orf9b in complex with human TOM70 suggests unusual
    virus-host interactions.
  findings: []
- id: PMID:34232536
  title: Interactomes of SARS-CoV-2 and human coronaviruses reveal host factors potentially
    affecting pathogenesis.
  findings: []
- id: PMID:34502139
  title: Phosphorylation of SARS-CoV-2 Orf9b Regulates Its Targeting to Two Binding Sites
    in TOM70 and Recruitment of Hsp90.
  findings: []
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular
    context.
  findings: []
- id: PMID:34942634
  title: Evolution of enhanced innate immune evasion by SARS-CoV-2.
  findings: []
- id: PMID:35391620
  title: The role of the individual TOM subunits in the association of PINK1 with depolarized
    mitochondria.
  findings: []
- id: PMID:36217030
  title: A comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19 pathobiology
    and potential host therapeutic targets.
  findings: []
- id: Reactome:R-HSA-5205661
  title: Pink1 is recruited from the cytoplasm to the mitochondria
  findings: []
- id: Reactome:R-HSA-9685281
  title: SARS-CoV-1 3a binds TRAF3 within NLRP3 inflammasome
  findings: []
- id: Reactome:R-HSA-9709663
  title: SARS-CoV-2 9b binds TOMM70
  findings: []
- id: Reactome:R-HSA-9709787
  title: SARS-CoV-1 9b binds TOMM70
  findings: []
- id: Reactome:R-HSA-9709842
  title: MAVS binds TOMM70
  findings: []
- id: Reactome:R-HSA-9709852
  title: MAVS:TOMM70 recruits HSP90:TBK1:IRF3
  findings: []
- id: file:human/TOMM70/TOMM70-deep-research-falcon.md
  title: Falcon deep research report for human TOMM70
  findings: []
core_functions:
- description: TOMM70 is an outer-mitochondrial-membrane receptor/adaptor that docks Hsp70/Hsp90-bound
    hydrophobic precursor proteins and promotes their handoff to the TOM import machinery
    rather than acting as the pore itself.
  supported_by:
  - reference_id: file:human/TOMM70/TOMM70-deep-research-falcon.md
    supporting_text: TOMM70 is best understood as a **surface receptor/adaptor** of the **TOM
      (translocase of the outer membrane)** import gateway
  - reference_id: file:human/TOMM70/TOMM70-deep-research-falcon.md
    supporting_text: Cytosolic **Hsp70/Hsp90** chaperones bind newly synthesized hydrophobic
      precursors to prevent aggregation and **deliver them to TOMM70**
  - reference_id: file:human/TOMM70/TOMM70-deep-research-falcon.md
    supporting_text: TOMM70 is anchored in the **outer mitochondrial membrane (OMM)** with
      its receptor domain facing the cytosol.
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  contributes_to_molecular_function:
    id: GO:0008320
    label: protein transmembrane transporter activity
  directly_involved_in:
  - id: GO:0070585
    label: protein localization to mitochondrion
  locations:
  - id: GO:0005741
    label: mitochondrial outer membrane
  in_complex:
    id: GO:0140596
    label: TOM complex
proposed_new_terms: []
suggested_questions:
- question: Which mammalian TOMM70 substrates require direct chaperone docking versus direct
    precursor contacts?
  experts: []
- question: How are TOMM70 import, MAVS signaling, and PINK1/Parkin quality-control roles
    separated by post-translational regulation?
  experts: []
suggested_experiments:
- hypothesis: TOMM70 TPR-domain mutants that disrupt Hsp70/Hsp90 docking selectively impair
    carrier/internal-signal precursor import while preserving TOM core assembly.
  description: Compare import of carrier-type substrates and presequence substrates in TOMM70
    knockout or knockdown cells rescued with wild-type versus chaperone-docking-defective
    TOMM70 variants.
- hypothesis: TOMM70 antiviral signaling can be separated from its import receptor activity
    by mutating MAVS/Hsp90 signaling interfaces outside the precursor handoff surface.
  description: Assay MAVS-induced IRF3 activation and mitochondrial precursor import in parallel
    for TOMM70 interface mutants.

Gene Description

Existing Annotations Review

Core Functions

TOMM70 is an outer-mitochondrial-membrane receptor/adaptor that docks Hsp70/Hsp90-bound hydrophobic precursor proteins and promotes their handoff to the TOM import machinery rather than acting as the pore itself.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human TOMM70 (UniProt O94826) functional annotation

1) Target verification (gene/protein identity)

2) Key concepts, definitions, and current understanding

2.1 TOMM70 as a mitochondrial protein import receptor (core function)

2.2 Domain architecture and chaperone docking

2.3 Subcellular localization beyond “mitochondrial surface”: foci and contact sites

2.4 TOMM70 as a signaling adaptor in innate immunity

2.5 TOMM70 in mitochondrial quality control and mitophagy

3) Recent developments (prioritizing 2023–2024)

3.1 2024: TOMM70 as a metabolic/immune node in human T cells (lactate → TOMM70 → MGAT1 import)

3.2 2024: Human genetic variation predicted to modulate TOMM70–SARS‑CoV‑2 ORF9b binding

3.3 2023–2024: TOMM70 highlighted as a multifunctional/regulatory TOM component

4) Current applications and real-world implementations

4.1 Diagnostic relevance: TOMM70 as a Mendelian mitochondrial disease gene

4.2 Therapeutic strategy concepts (preclinical): modulating TOMM70-linked pathways

4.3 Cell therapy context (Treg function)

5) Expert opinions and authoritative synthesis (how experts frame TOMM70)

6) Quantitative/statistical findings from recent and key studies

6.1 Structural/domain quantitative descriptors

6.2 Import-system scale

6.3 Quantitative variant effects and population frequencies relevant to TOMM70–ORF9b interaction (2024)

6.4 Quantitative/statistical evidence in the 2024 Treg study

7) Visual evidence (figures) supporting mechanistic understanding

8) Summary functional annotation (most defensible “primary function”)

Evidence-mapped reference table

Key cited sources (publication date; URL)

Citations

📄 View Raw YAML