TOMM6

GO Term	Evidence	Action	Reason
GO:0005739 mitochondrion	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: TOMM6 is a mitochondrial protein, but the annotation is less specific than the well-supported mitochondrial outer membrane/TOM complex localization. Reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
GO:0005741 mitochondrial outer membrane	IEA GO_REF:0000044	ACCEPT	Summary: Correct UniProt-derived localization. Falcon research summarizes TOMM6 as a single-pass outer mitochondrial membrane component of the TOM core. Supporting Evidence: file:human/TOMM6/TOMM6-deep-research-falcon.md Human TOMM6 is an OMM component of TOM.
GO:0005742 mitochondrial outer membrane translocase complex	IEA GO_REF:0000002	ACCEPT	Summary: Correct complex-level annotation. TOMM6 is one of the small Tom subunits of the TOM core with TOMM40, TOMM22, TOMM5, and TOMM7.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Generic binary-interactome protein binding does not capture TOMM6's specific role as a structural/regulatory TOM core subunit. Reason: Protein binding is uninformative for TOMM6; the curated function is TOM complex organization at the mitochondrial outer membrane.
GO:0005739 mitochondrion	IDA GO_REF:0000052	MARK AS OVER ANNOTATED	Summary: Correct but too general. TOMM6 is specifically an outer membrane TOM core subunit. Reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
GO:0005741 mitochondrial outer membrane	NAS PMID:18331822 Identification of Tom5 and Tom6 in the preprotein translocas...	ACCEPT	Summary: Kato and Mihara identified human Tom6 in the outer membrane TOM preprotein translocase complex; this agrees with structural/review evidence summarized by Falcon.
GO:0045040 protein insertion into mitochondrial outer membrane	NAS PMID:18331822 Identification of Tom5 and Tom6 in the preprotein translocas...	MODIFY	Summary: The broad direction of the annotation is related to TOMM6 biology, but TOMM6 is not itself an insertase. Evidence better supports a role in TOM core assembly, stability, and oligomerization. Reason: Replace the insertion process with TOM complex assembly/stability, which better matches the small Tom6 subunit role. Proposed replacements: mitochondrial outer membrane translocase complex assembly
GO:0140596 TOM complex	NAS PMID:18331822 Identification of Tom5 and Tom6 in the preprotein translocas...	ACCEPT	Summary: Correct specific complex annotation. TOMM6 is a small TOM core subunit positioned against TOMM40 and coupled to TOMM22 in structural models.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	MARK AS OVER ANNOTATED	Summary: High-throughput mitochondrial proteomics supports mitochondrial localization, but this is less specific than the mitochondrial outer membrane/TOM complex annotations. Reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-5205661	ACCEPT	Summary: Reactome places TOMM6 at the mitochondrial outer membrane in TOM/PINK1 pathway context. This matches the structural TOM core localization.

Deep Research

Falcon

(TOMM6-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 30 citations 2026-05-11T11:11:15.723692

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 TOMM6 (UniProt Q96B49) — functional annotation

0) Target verification (critical identity checks)

The evidence retrieved aligns with the provided UniProt target: human TOMM6 (Tom6 family), described as a very small TOM complex subunit (“small TOM”/microprotein) and not an enzyme or transporter with an independent catalytic reaction. Multiple sources describe Tom6/TOMM6 as an α-helical single-pass outer mitochondrial membrane (OMM) protein that participates in the TOM (translocase of the outer membrane) protein-import machinery together with TOMM40 (pore) and TOMM22 (core receptor/adaptor). (kamradt2023mitochondrialmicroproteinscritical pages 1-4, guan2021structuralinsightsinto pages 1-3, araiso2022structuraloverviewof pages 1-3)

1) Key concepts and definitions (current understanding)

1.1 The TOM complex and “small TOM” subunits

The TOM complex is the canonical entry gate for import of the vast majority of nuclear-encoded mitochondrial proteins across the OMM. Structurally, it is built around the β-barrel channel Tom40 (TOMM40) and several single-pass α-helical subunits, including receptor/adaptor subunits (Tom20/Tom22/Tom70) and “small TOM” subunits Tom5/Tom6/Tom7. (araiso2022structuraloverviewof pages 1-3)

In this framework, TOMM6 is best defined as an auxiliary structural/regulatory subunit that supports assembly, stability, and oligomerization of the TOM core rather than directly binding and transporting substrates as a stand-alone importer. (bayne2024mitochondrialproteinimport pages 32-36, kamradt2023mitochondrialmicroproteinscritical pages 1-4)

1.2 TOMM6 molecular role (definition of function)

Current functional descriptions emphasize two related roles:
1) Stabilizing/assembling the TOM core by binding the outer wall of Tom40. (araiso2022structuraloverviewof pages 3-5, guan2021structuralinsightsinto pages 1-3)
2) Helping couple Tom22 to the Tom40 pore, described in a 2023 review as TOMM6 “anchoring TOMM22 to the TOMM40 pore.” (kamradt2023mitochondrialmicroproteinscritical pages 1-4)

Thus, TOMM6’s “primary function” is structural/organizational within the TOM complex, supporting efficient mitochondrial precursor translocation via TOMM40. (bayne2024mitochondrialproteinimport pages 32-36, kamradt2023mitochondrialmicroproteinscritical pages 1-4)

2) Recent developments and latest research (prioritize 2023–2024)

2.1 2023: TOMM6 as a mitochondrial microprotein subunit with an anchoring role

A 2023 review of mitochondrial microproteins summarizes TOMM6 as a 74-aa microprotein that associates with TOMM40, contributes to TOM channel stability, and has an “additional role” in anchoring TOMM22 to the TOMM40 pore. The same review states that siRNA targeting of the small TOMM proteins (TOMM5/6/7) destabilizes TOM complex proteins, supporting an assembly/stability role. (kamradt2023mitochondrialmicroproteinscritical pages 1-4)

Publication details: Kamradt ML, Makarewich CA. Am J Physiol Cell Physiol. Oct 2023. https://doi.org/10.1152/ajpcell.00189.2023 (kamradt2023mitochondrialmicroproteinscritical pages 1-4)

2.2 2024: TOM complex architecture is conserved; small Tom subunits regulate stability/assembly

A 2024 review text focused on mitochondrial protein import and PINK1-mediated quality control describes Tom6 (with Tom5/Tom7) as part of constitutive accessory factors that form helices on the exterior of the TOM complex and regulate stability, assembly, and oligomerization. It also summarizes that TOM core architecture is highly conserved between yeast and human, with a dominant dimeric arrangement. (bayne2024mitochondrialproteinimport pages 32-36)

Publication details: Bayne AN. Mitochondrial protein import and the role of PINK1 in mitochondrial quality control (2024; journal not resolved in retrieved text). (bayne2024mitochondrialproteinimport pages 32-36)

Note: The most detailed TOMM6 mechanistic advances in our retrieved corpus are from 2021–2022 structural work; 2023–2024 sources mainly consolidate and contextualize TOMM6’s role as a small TOM subunit/microprotein in a stable conserved machine. (kamradt2023mitochondrialmicroproteinscritical pages 1-4, bayne2024mitochondrialproteinimport pages 32-36)

3) Molecular function, localization, topology, and pathways

3.1 Subcellular localization and topology

Human TOMM6 is an OMM component of TOM. A primary cryo-EM study and structural reviews describe Tom6 as a single-pass α-helical membrane protein (single transmembrane segment) positioned on the exterior of the Tom40 β-barrel, consistent with an accessory structural role. (guan2021structuralinsightsinto pages 1-3, araiso2022structuraloverviewof pages 3-5, araiso2022structuraloverviewof pages 1-3)

3.2 Interaction partners and placement within the TOM core

Core membership: The TOM “core complex” is commonly described as TOMM40 plus TOMM22 plus small Tom proteins (Tom5/6/7); receptor subunits Tom20/Tom70 can dissociate in some preparations. A 2021 human TOM cryo-EM structure built Tom40, Tom22, Tom5, Tom6, and Tom7 (Tom20/Tom70 were not resolved in the core). (guan2021structuralinsightsinto pages 1-3)

Specific partner interactions inferred/observed:
- Tom6 contacts the Tom40 β-barrel, especially around the β13–β15 region, primarily via hydrophobic interactions. (araiso2022structuraloverviewof pages 3-5, guan2021structuralinsightsinto pages 3-4)
- Tom6 has an inverted L-shape with a cytosolic helix segment (α1) that can contact Tom22, supporting the notion that Tom6 helps incorporate/position Tom22 in the assembled TOM core. (guan2021structuralinsightsinto pages 3-4)
- A 2023 review explicitly states TOMM6 helps anchor TOMM22 to TOMM40. (kamradt2023mitochondrialmicroproteinscritical pages 1-4)

3.3 Mechanistic role in mitochondrial protein import

TOMM6 is not itself the pore; rather it supports the protein import pathway by maintaining TOM structural integrity and assembly state.
- Reviews describe Tom5/Tom6/Tom7 as exterior helices that regulate TOM complex stability/assembly/oligomerization, which is required for high-throughput import across the OMM. (bayne2024mitochondrialproteinimport pages 32-36)
- Structural reviews describe the TOM dimer as two Tom40 barrels with accessory subunits surrounding them; Tom6 is one of the small Tom proteins bound to Tom40’s outer wall. (araiso2022structuraloverviewof pages 1-3, araiso2022structuraloverviewof pages 3-5)

3.4 Pathway connections: mitochondrial quality control / mitophagy context

The retrieved disease/quality-control literature is largely TOM-complex-level, not TOMM6-specific.
- The TOM machinery is integrated into mitophagy signaling: PINK1 forms complexes with TOM components (notably TOMM70/TOMM22/TOMM20/TOMM40), and TOM levels can modulate PINK1–PRKN mediated clearance in some contexts. (heinemeyer2019underappreciatedrolesof pages 9-10, heinemeyer2019underappreciatedrolesof pages 10-11)
- No retrieved excerpt demonstrated a TOMM6-specific biochemical role in PINK1 docking or Parkin recruitment; TOMM6’s role here is best framed as enabling proper TOM assembly/stability that would be prerequisite for these events. (bayne2024mitochondrialproteinimport pages 32-36, heinemeyer2019underappreciatedrolesof pages 10-11)

4) High-confidence structural data and quantitative details (key statistics)

4.1 Cryo-EM resolutions and assembly states (human TOM)

A major primary study solved human TOM assemblies:
- Dimeric TOM core: 3.0 Å resolution (near-atomic). (guan2021structuralinsightsinto pages 1-3)
- Trimeric TOM: 4.3 Å after C2 symmetry; 6.3 Å overall in a C1 map (lower detail, with helical subunits not confidently modeled in that trimer reconstruction). (guan2021structuralinsightsinto pages 3-4, guan2021structuralinsightsinto pages 1-3)

These values provide quantitative support that Tom6 placement and lipid-mediated contacts are derived from near-atomic structural information in the dimeric core. (guan2021structuralinsightsinto pages 1-3)

Publication details: Guan Z et al. Cell Discovery. Apr 2021. https://doi.org/10.1038/s41421-021-00252-7 (guan2021structuralinsightsinto pages 1-3)

4.2 Lipid-mediated Tom6–Tom40 bridging (PL3)

The 2021 structure reports a phospholipid-like density (PL3) bridging Tom6 and Tom40, with residue-level contacts:
- PL3 contacts Tom6 R38 and R43
- PL3 contacts Tom40 S320, W322, R348
This supports a mechanism in which specific lipids help stabilize Tom6 association with Tom40 and potentially influence assembly dynamics. (guan2021structuralinsightsinto pages 1-3, guan2021structuralinsightsinto pages 3-4)

A figure from this work directly depicts the TOM core architecture and the PL3 bridge between Tom6 and Tom40. (guan2021structuralinsightsinto media 976d9995)

5) Regulation and real-world implementations

5.1 Ubiquitin-system regulation of mitochondrial import (complex-level; not TOMM6-specific)

A key mechanistic study shows that mitochondrial ubiquitin machinery dynamically regulates TOM-dependent import. The data include several quantitative/proteomics statistics:
- Upon USP30 inhibitor treatment, mass spectrometry showed altered ubiquitination of 9 proteins at 30 min and 489 proteins at 2 h; many changes were recapitulated in USP30 knockout cells. (phu2020dynamicregulationof pages 4-7)
- Comparing WT vs USP30 KO without inhibitor, 36 of 61 differentially ubiquitinated mitochondrial proteins were increased in KO cells, with 34 of these being intramitochondrial proteins. (phu2020dynamicregulationof pages 3-4)
- USP30 inhibition increased ubiquitinated TOM20 (Ub-TOM20) with an EC50 of 2.45 mM (as reported in the excerpt), and USP30 co-immunoprecipitated with TOM complex subunits TOM20, TOM40, and TOM70 in the retrieved pages. (phu2020dynamicregulationof pages 4-7, phu2020dynamicregulationof pages 3-4)

Although TOM complex subunits are discussed as regulated targets, the retrieved excerpts do not establish TOMM6 as a direct ubiquitination substrate; therefore the safest statement is that TOMM6 is embedded in a TOM complex whose activity and subunit abundances can be influenced by ubiquitin enzymes acting at TOM. (phu2020dynamicregulationof pages 1-3, phu2020dynamicregulationof pages 9-10)

Publication details: Phu L et al. Molecular Cell. Mar 2020. https://doi.org/10.1016/j.molcel.2020.02.012 (phu2020dynamicregulationof pages 1-3)

5.2 Current applications / implementations

No TOMM6-specific clinical applications, assays, or targeted drugs were identified in the retrieved evidence. Current “real-world” implementation is primarily structural and mechanistic:
- TOMM6 is part of the experimentally reconstituted and structurally resolved human TOM core that underpins mitochondrial protein import studies and informs mechanistic models of import and quality control. (guan2021structuralinsightsinto pages 1-3, guan2021structuralinsightsinto media 976d9995)
- Import regulation through ubiquitin enzymes (e.g., USP30/MARCH5/MUL1) is actively investigated as a translational entry point for modulating mitochondrial protein homeostasis; TOMM6 relevance is indirect through its contribution to TOM core integrity. (phu2020dynamicregulationof pages 1-3, phu2020dynamicregulationof pages 4-7)

6) Disease associations, cancer links, and the “OBTP” alias (strength of evidence)

6.1 Evidence for TOMM6-specific disease links is limited

A 2019 review broadly connects TOM/TIM subunits to neurodegeneration, cardiovascular disease, and cancers, but the detailed mechanistic and genetic evidence in the retrieved pages focuses on other TOM components (especially TOMM40, and also TOMM20/TOMM22/TOMM70). It notes decreased TOMM40 in PD brain and TOM involvement in PINK1–PRKN mitophagy, and it states generally that increased mRNA/protein levels of complex subunits are found in cancers; however, it does not provide TOMM6-specific causal evidence in the retrieved excerpts. (heinemeyer2019underappreciatedrolesof pages 10-11, heinemeyer2019underappreciatedrolesof pages 1-2)

Publication details: Heinemeyer T et al. DNA Cell Biol. Jan 2019. https://doi.org/10.1089/dna.2018.4292 (heinemeyer2019underappreciatedrolesof pages 1-2)

6.2 Open Targets: low-evidence associations from functional screens

Open Targets lists TOMM6 associations with broad disease categories (e.g., “neurodegenerative disease”) supported by functional screen evidence (e.g., CRISPRi survival screens) and literature linkage (PubMed 34031600 in the Open Targets evidence rows). This should be interpreted as hypothesis-generating rather than establishing mechanism or causality for TOMM6 in disease. (OpenTargets Search: -TOMM6)

6.3 “OBTP” (overexpressed breast tumor protein) alias

The alternative name “OBTP” suggests historical cancer-related naming, but within the retrieved evidence set, there is no strong primary study validating TOMM6 as a breast cancer biomarker/driver, and cancer-related statements are mostly general to TOM/TIM complex subunits without TOMM6-specific support. Therefore, the cancer relevance of TOMM6 remains unresolved/limited based on the evidence retrieved here. (heinemeyer2019underappreciatedrolesof pages 1-2, heinemeyer2019underappreciatedrolesof pages 12-13)

7) Expert synthesis / interpretation

Across authoritative structural and review sources, TOMM6 emerges as a microprotein accessory subunit that helps organize the TOM core complex at the OMM. The most concrete mechanistic insight is structural: Tom6’s placement on Tom40 (β13–β15 region), its cytosolic helix proximity to Tom22, and lipid-mediated bridging (PL3) provide a plausible physical basis for the repeatedly cited “assembly/stability” and “Tom22 anchoring” roles. (guan2021structuralinsightsinto pages 3-4, kamradt2023mitochondrialmicroproteinscritical pages 1-4, guan2021structuralinsightsinto pages 1-3, guan2021structuralinsightsinto media 976d9995)

However, compared with receptor and pore subunits (TOM20/TOM22/TOM40/TOM70), there is less direct disease-genetics and regulatory biochemistry specifically attributed to TOMM6 in the retrieved literature. Current evidence supports TOMM6 as a necessary part of the core machine; disease links are presently stronger at the level of the TOM complex or other subunits. (heinemeyer2019underappreciatedrolesof pages 1-2, phu2020dynamicregulationof pages 1-3)

8) Summary table of evidence

The following table consolidates the main functional-annotation claims with evidence types and URLs/DOIs.

Category	Key points	Evidence type	Key references with year and DOI/URL
Identity/domains	Human TOMM6 corresponds to UniProt Q96B49 and is the Tom6-family mitochondrial import receptor subunit homolog. In the literature summarized here, TOMM6 is consistently treated as a small TOM complex subunit/microprotein of 74 aa rather than an enzyme or transporter with an independent catalytic activity (kamradt2023mitochondrialmicroproteinscritical pages 1-4, araiso2022structuraloverviewof pages 1-3).	Review, structural review	Kamradt & Makarewich 2023, https://doi.org/10.1152/ajpcell.00189.2023; Araiso & Endo 2022, https://doi.org/10.2142/biophysico.bppb-v19.0022
Localization/topology	TOMM6 is an outer mitochondrial membrane TOM subunit. Structural/review evidence describes it as an α-helical single-pass membrane protein; Guan et al. place Tom6 at the Tom40 barrel with an inverted L-shaped architecture including a membrane helix and a cytosolic α1 segment that can contact Tom22 (guan2021structuralinsightsinto pages 3-4, araiso2022structuraloverviewof pages 3-5, guan2021structuralinsightsinto pages 1-3, araiso2022structuraloverviewof pages 1-3).	Cryo-EM/MD, structural review	Guan et al. 2021, https://doi.org/10.1038/s41421-021-00252-7; Araiso & Endo 2022, https://doi.org/10.2142/biophysico.bppb-v19.0022
Complex membership/interactions	TOMM6 is one of the three “small TOM” subunits (Tom5/6/7) in the TOM core complex with TOMM40 and TOMM22. It interacts closely with TOMM40 and is reported to help anchor/stimulate assembly of TOMM22 with TOMM40; mammalian TOM core architecture is conserved with yeast (guan2021structuralinsightsinto pages 3-4, bayne2024mitochondrialproteinimport pages 32-36, kamradt2023mitochondrialmicroproteinscritical pages 1-4, akram2025proximitylabelingapproaches pages 19-22).	Cryo-EM/MD, review	Guan et al. 2021, https://doi.org/10.1038/s41421-021-00252-7; Kamradt & Makarewich 2023, https://doi.org/10.1152/ajpcell.00189.2023; Bayne 2024 (review text in evidence)
Mechanistic role in import	TOMM6 does not itself transport substrate independently; rather, it supports the TOM import channel by stabilizing/assembling the core and thereby enabling efficient passage of mitochondrial precursor proteins through TOMM40. Reviews state TOMM6, TOMM5, and TOMM7 regulate TOM stability, assembly, and oligomerization, and siRNA against the small TOMMs destabilizes TOM complex proteins (bayne2024mitochondrialproteinimport pages 32-36, kamradt2023mitochondrialmicroproteinscritical pages 1-4).	Review, perturbation summary	Kamradt & Makarewich 2023, https://doi.org/10.1152/ajpcell.00189.2023; Araiso & Endo 2022, https://doi.org/10.2142/biophysico.bppb-v19.0022
Structural evidence	Human TOM cryo-EM structures resolved the dimeric TOM core at 3.0 Å and a trimeric assembly at 4.3 Å; a lower-resolution 6.3 Å C1 trimer map was also reported. Modeled human core subunits include Tom40, Tom22, Tom5, Tom6, and Tom7, while Tom20/Tom70 were not resolved in the core preparation (guan2021structuralinsightsinto pages 3-4, guan2021structuralinsightsinto pages 1-3, guan2021structuralinsightsinto pages 4-5).	Cryo-EM	Guan et al. 2021, https://doi.org/10.1038/s41421-021-00252-7
Structural evidence	Tom6 is positioned near β13–β15 of Tom40 and contacts Tom40 mainly through hydrophobic interactions. A phospholipid-like density PL3 bridges Tom6 residues R38/R43 to Tom40 residues S320/W322/R348, and MD simulations suggested PL3 increases Tom6 dynamics, supporting a lipid-mediated assembly/stability role (guan2021structuralinsightsinto pages 3-4, guan2021structuralinsightsinto pages 1-3, guan2021structuralinsightsinto media 976d9995).	Cryo-EM/MD	Guan et al. 2021, https://doi.org/10.1038/s41421-021-00252-7
Regulation	Direct TOMM6-specific ubiquitination/regulatory evidence was not identified in the gathered material. At the complex level, USP30, MARCH5, and MUL1 dynamically regulate TOM-dependent import, and USP30 knockout mice show reduced abundance of TOM complex subunits across tissues; TOM20 is a named ubiquitin-sensitive TOM substrate, but TOMM6-specific modification was not shown in the retrieved excerpts (phu2020dynamicregulationof pages 9-10, phu2020dynamicregulationof pages 1-3, phu2020dynamicregulationof pages 4-7, phu2020dynamicregulationof pages 3-4).	Proteomics, ubiquitin biology	Phu et al. 2020, https://doi.org/10.1016/j.molcel.2020.02.012
Disease/phenotype links	Direct disease causality for TOMM6 was limited in the gathered literature. Reviews link TOM machinery broadly to neurodegeneration, mitophagy, cardiovascular disease, and cancer, but the strongest specific evidence is for TOMM40/TOMM20/TOMM22/TOMM70 rather than TOMM6; Open Targets shows only low-evidence disease associations for TOMM6 from functional screens, not established Mendelian disease links (heinemeyer2019underappreciatedrolesof pages 9-10, heinemeyer2019underappreciatedrolesof pages 1-2, heinemeyer2019underappreciatedrolesof pages 10-11, OpenTargets Search: -TOMM6).	Review, genetics/database	Heinemeyer et al. 2019, https://doi.org/10.1089/dna.2018.4292; Open Targets context (OpenTargets Search: -TOMM6)
Disease/phenotype links	The alias “OBTP” reflects older naming (“overexpressed breast tumor protein”), but the gathered evidence did not provide robust primary support that TOMM6 is a validated breast cancer driver or biomarker. Cancer-related statements in the reviewed literature refer generally to increased expression of some TOM/TIM complex subunits, without TOMM6-specific validation in the retrieved excerpts (heinemeyer2019underappreciatedrolesof pages 1-2, heinemeyer2019underappreciatedrolesof pages 12-13).	Review	Heinemeyer et al. 2019, https://doi.org/10.1089/dna.2018.4292
Applications	Current real-world relevance is mainly mechanistic and translational: TOMM6 helps define human TOM complex architecture used in mitochondrial import research, and TOM-complex regulation is being studied for mitophagy/neurodegeneration therapeutics. No TOMM6-targeted drugs or clinical implementations were identified in the gathered evidence (guan2021structuralinsightsinto pages 1-3, heinemeyer2019underappreciatedrolesof pages 10-11, phu2020dynamicregulationof pages 4-7).	Structural biology, disease-mechanism research	Guan et al. 2021, https://doi.org/10.1038/s41421-021-00252-7; Phu et al. 2020, https://doi.org/10.1016/j.molcel.2020.02.012; Heinemeyer et al. 2019, https://doi.org/10.1089/dna.2018.4292

Table: This table summarizes the evidence-based functional annotation of human TOMM6/Q96B49, including localization, TOM complex role, structural findings, regulation, and disease relevance. It is useful as a compact reference because direct TOMM6-specific literature is limited and much of the strongest evidence comes from TOM complex structural studies.

Key primary and review sources (URLs; publication dates)

Guan Z et al. Apr 2021. Cell Discovery. “Structural insights into assembly of human mitochondrial translocase TOM complex.” https://doi.org/10.1038/s41421-021-00252-7 (guan2021structuralinsightsinto pages 1-3)
Araiso Y, Endo T. Jun 2022. Biophysics and Physicobiology. “Structural overview of the translocase of the mitochondrial outer membrane complex.” https://doi.org/10.2142/biophysico.bppb-v19.0022 (araiso2022structuraloverviewof pages 1-3)
Kamradt ML, Makarewich CA. Oct 2023. Am J Physiol Cell Physiol. “Mitochondrial microproteins…” https://doi.org/10.1152/ajpcell.00189.2023 (kamradt2023mitochondrialmicroproteinscritical pages 1-4)
Bayne AN. 2024. “Mitochondrial protein import and the role of PINK1…” (journal not resolved in retrieved text). (bayne2024mitochondrialproteinimport pages 32-36)
Phu L et al. Mar 2020. Molecular Cell. “Dynamic regulation of mitochondrial import by the ubiquitin system.” https://doi.org/10.1016/j.molcel.2020.02.012 (phu2020dynamicregulationof pages 1-3)
Heinemeyer T et al. Jan 2019. DNA Cell Biol. “Underappreciated roles…” https://doi.org/10.1089/dna.2018.4292 (heinemeyer2019underappreciatedrolesof pages 1-2)

References

(kamradt2023mitochondrialmicroproteinscritical pages 1-4): Michael L. Kamradt and Catherine A. Makarewich. Mitochondrial microproteins: critical regulators of protein import, energy production, stress response pathways, and programmed cell death. American Journal of Physiology-Cell Physiology, 325:C807-C816, Oct 2023. URL: https://doi.org/10.1152/ajpcell.00189.2023, doi:10.1152/ajpcell.00189.2023. This article has 12 citations.
(guan2021structuralinsightsinto pages 1-3): Zeyuan Guan, Ling Yan, Qiang Wang, Liangbo Qi, Sixing Hong, Zhou Gong, Chuangye Yan, and Ping Yin. Structural insights into assembly of human mitochondrial translocase tom complex. Cell Discovery, Apr 2021. URL: https://doi.org/10.1038/s41421-021-00252-7, doi:10.1038/s41421-021-00252-7. This article has 50 citations and is from a peer-reviewed journal.
(araiso2022structuraloverviewof pages 1-3): Yuhei Araiso and Toshiya Endo. Structural overview of the translocase of the mitochondrial outer membrane complex. Biophysics and Physicobiology, 19:n/a, Jun 2022. URL: https://doi.org/10.2142/biophysico.bppb-v19.0022, doi:10.2142/biophysico.bppb-v19.0022. This article has 21 citations.
(bayne2024mitochondrialproteinimport pages 32-36): AN Bayne. Mitochondrial protein import and the role of pink1 in mitochondrial quality control. Unknown journal, 2024.
(araiso2022structuraloverviewof pages 3-5): Yuhei Araiso and Toshiya Endo. Structural overview of the translocase of the mitochondrial outer membrane complex. Biophysics and Physicobiology, 19:n/a, Jun 2022. URL: https://doi.org/10.2142/biophysico.bppb-v19.0022, doi:10.2142/biophysico.bppb-v19.0022. This article has 21 citations.
(guan2021structuralinsightsinto pages 3-4): Zeyuan Guan, Ling Yan, Qiang Wang, Liangbo Qi, Sixing Hong, Zhou Gong, Chuangye Yan, and Ping Yin. Structural insights into assembly of human mitochondrial translocase tom complex. Cell Discovery, Apr 2021. URL: https://doi.org/10.1038/s41421-021-00252-7, doi:10.1038/s41421-021-00252-7. This article has 50 citations and is from a peer-reviewed journal.
(heinemeyer2019underappreciatedrolesof pages 9-10): Thea Heinemeyer, Monique Stemmet, Soraya Bardien, and Annika Neethling. Underappreciated roles of the translocase of the outer and inner mitochondrial membrane protein complexes in human disease. DNA and cell biology, 38 1:23-40, Jan 2019. URL: https://doi.org/10.1089/dna.2018.4292, doi:10.1089/dna.2018.4292. This article has 43 citations and is from a peer-reviewed journal.
(heinemeyer2019underappreciatedrolesof pages 10-11): Thea Heinemeyer, Monique Stemmet, Soraya Bardien, and Annika Neethling. Underappreciated roles of the translocase of the outer and inner mitochondrial membrane protein complexes in human disease. DNA and cell biology, 38 1:23-40, Jan 2019. URL: https://doi.org/10.1089/dna.2018.4292, doi:10.1089/dna.2018.4292. This article has 43 citations and is from a peer-reviewed journal.
(guan2021structuralinsightsinto media 976d9995): Zeyuan Guan, Ling Yan, Qiang Wang, Liangbo Qi, Sixing Hong, Zhou Gong, Chuangye Yan, and Ping Yin. Structural insights into assembly of human mitochondrial translocase tom complex. Cell Discovery, Apr 2021. URL: https://doi.org/10.1038/s41421-021-00252-7, doi:10.1038/s41421-021-00252-7. This article has 50 citations and is from a peer-reviewed journal.
(phu2020dynamicregulationof pages 4-7): Lilian Phu, Christopher M. Rose, Joy S. Tea, Christopher E. Wall, Erik Verschueren, Tommy K. Cheung, Donald S. Kirkpatrick, and Baris Bingol. Dynamic regulation of mitochondrial import by the ubiquitin system. Molecular cell, 77 5:1107-1123.e10, Mar 2020. URL: https://doi.org/10.1016/j.molcel.2020.02.012, doi:10.1016/j.molcel.2020.02.012. This article has 163 citations and is from a highest quality peer-reviewed journal.
(phu2020dynamicregulationof pages 3-4): Lilian Phu, Christopher M. Rose, Joy S. Tea, Christopher E. Wall, Erik Verschueren, Tommy K. Cheung, Donald S. Kirkpatrick, and Baris Bingol. Dynamic regulation of mitochondrial import by the ubiquitin system. Molecular cell, 77 5:1107-1123.e10, Mar 2020. URL: https://doi.org/10.1016/j.molcel.2020.02.012, doi:10.1016/j.molcel.2020.02.012. This article has 163 citations and is from a highest quality peer-reviewed journal.
(phu2020dynamicregulationof pages 1-3): Lilian Phu, Christopher M. Rose, Joy S. Tea, Christopher E. Wall, Erik Verschueren, Tommy K. Cheung, Donald S. Kirkpatrick, and Baris Bingol. Dynamic regulation of mitochondrial import by the ubiquitin system. Molecular cell, 77 5:1107-1123.e10, Mar 2020. URL: https://doi.org/10.1016/j.molcel.2020.02.012, doi:10.1016/j.molcel.2020.02.012. This article has 163 citations and is from a highest quality peer-reviewed journal.
(phu2020dynamicregulationof pages 9-10): Lilian Phu, Christopher M. Rose, Joy S. Tea, Christopher E. Wall, Erik Verschueren, Tommy K. Cheung, Donald S. Kirkpatrick, and Baris Bingol. Dynamic regulation of mitochondrial import by the ubiquitin system. Molecular cell, 77 5:1107-1123.e10, Mar 2020. URL: https://doi.org/10.1016/j.molcel.2020.02.012, doi:10.1016/j.molcel.2020.02.012. This article has 163 citations and is from a highest quality peer-reviewed journal.
(heinemeyer2019underappreciatedrolesof pages 1-2): Thea Heinemeyer, Monique Stemmet, Soraya Bardien, and Annika Neethling. Underappreciated roles of the translocase of the outer and inner mitochondrial membrane protein complexes in human disease. DNA and cell biology, 38 1:23-40, Jan 2019. URL: https://doi.org/10.1089/dna.2018.4292, doi:10.1089/dna.2018.4292. This article has 43 citations and is from a peer-reviewed journal.
(OpenTargets Search: -TOMM6): Open Targets Query (-TOMM6, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(heinemeyer2019underappreciatedrolesof pages 12-13): Thea Heinemeyer, Monique Stemmet, Soraya Bardien, and Annika Neethling. Underappreciated roles of the translocase of the outer and inner mitochondrial membrane protein complexes in human disease. DNA and cell biology, 38 1:23-40, Jan 2019. URL: https://doi.org/10.1089/dna.2018.4292, doi:10.1089/dna.2018.4292. This article has 43 citations and is from a peer-reviewed journal.
(akram2025proximitylabelingapproaches pages 19-22): S Akram. Proximity labeling approaches to mitochondrial import receptors tomm20 and tomm70. Unknown journal, 2025.
(guan2021structuralinsightsinto pages 4-5): Zeyuan Guan, Ling Yan, Qiang Wang, Liangbo Qi, Sixing Hong, Zhou Gong, Chuangye Yan, and Ping Yin. Structural insights into assembly of human mitochondrial translocase tom complex. Cell Discovery, Apr 2021. URL: https://doi.org/10.1038/s41421-021-00252-7, doi:10.1038/s41421-021-00252-7. This article has 50 citations and is from a peer-reviewed journal.

Citations

araiso2022structuraloverviewof pages 1-3
kamradt2023mitochondrialmicroproteinscritical pages 1-4
bayne2024mitochondrialproteinimport pages 32-36
guan2021structuralinsightsinto pages 1-3
guan2021structuralinsightsinto pages 3-4
phu2020dynamicregulationof pages 4-7
phu2020dynamicregulationof pages 3-4
phu2020dynamicregulationof pages 1-3
heinemeyer2019underappreciatedrolesof pages 1-2
araiso2022structuraloverviewof pages 3-5
heinemeyer2019underappreciatedrolesof pages 9-10
heinemeyer2019underappreciatedrolesof pages 10-11
phu2020dynamicregulationof pages 9-10
heinemeyer2019underappreciatedrolesof pages 12-13
akram2025proximitylabelingapproaches pages 19-22
guan2021structuralinsightsinto pages 4-5
https://doi.org/10.1152/ajpcell.00189.2023
https://doi.org/10.1038/s41421-021-00252-7
https://doi.org/10.1016/j.molcel.2020.02.012
https://doi.org/10.1089/dna.2018.4292
https://doi.org/10.1152/ajpcell.00189.2023;
https://doi.org/10.2142/biophysico.bppb-v19.0022
https://doi.org/10.1038/s41421-021-00252-7;
https://doi.org/10.1089/dna.2018.4292;
https://doi.org/10.1016/j.molcel.2020.02.012;
https://doi.org/10.1152/ajpcell.00189.2023,
https://doi.org/10.1038/s41421-021-00252-7,
https://doi.org/10.2142/biophysico.bppb-v19.0022,
https://doi.org/10.1089/dna.2018.4292,
https://doi.org/10.1016/j.molcel.2020.02.012,

📄 View Raw YAML

id: Q96B49
gene_symbol: TOMM6
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  TOMM6 is a small single-pass mitochondrial outer membrane subunit of the TOM
  translocase core. It is not an independent transporter or enzyme; instead it
  helps organize and stabilize the TOMM40/TOMM22-containing import channel,
  including anchoring/positioning TOMM22 and supporting TOM core assembly and
  oligomerization.
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      TOMM6 is a mitochondrial protein, but the annotation is less specific than
      the well-supported mitochondrial outer membrane/TOM complex localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
    additional_reference_ids:
    - file:human/TOMM6/TOMM6-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      Correct UniProt-derived localization. Falcon research summarizes TOMM6 as
      a single-pass outer mitochondrial membrane component of the TOM core.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM6/TOMM6-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TOMM6/TOMM6-deep-research-falcon.md
      supporting_text: "Human TOMM6 is an OMM component of TOM."
- term:
    id: GO:0005742
    label: mitochondrial outer membrane translocase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      Correct complex-level annotation. TOMM6 is one of the small Tom subunits
      of the TOM core with TOMM40, TOMM22, TOMM5, and TOMM7.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM6/TOMM6-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: >-
      Generic binary-interactome protein binding does not capture TOMM6's
      specific role as a structural/regulatory TOM core subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is uninformative for TOMM6; the curated function is TOM
      complex organization at the mitochondrial outer membrane.
    additional_reference_ids:
    - file:human/TOMM6/TOMM6-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. TOMM6 is specifically an outer membrane TOM core
      subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
    additional_reference_ids:
    - file:human/TOMM6/TOMM6-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: NAS
  original_reference_id: PMID:18331822
  review:
    summary: >-
      Kato and Mihara identified human Tom6 in the outer membrane TOM
      preprotein translocase complex; this agrees with structural/review
      evidence summarized by Falcon.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM6/TOMM6-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 broad direction of the annotation is related to TOMM6 biology, but
      TOMM6 is not itself an insertase. Evidence better supports a role in TOM
      core assembly, stability, and oligomerization.
    action: MODIFY
    reason: >-
      Replace the insertion process with TOM complex assembly/stability, which
      better matches the small Tom6 subunit role.
    proposed_replacement_terms:
    - id: GO:0070096
      label: mitochondrial outer membrane translocase complex assembly
    additional_reference_ids:
    - file:human/TOMM6/TOMM6-deep-research-falcon.md
- term:
    id: GO:0140596
    label: TOM complex
  evidence_type: NAS
  original_reference_id: PMID:18331822
  review:
    summary: >-
      Correct specific complex annotation. TOMM6 is a small TOM core subunit
      positioned against TOMM40 and coupled to TOMM22 in structural models.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM6/TOMM6-deep-research-falcon.md
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  review:
    summary: >-
      High-throughput mitochondrial proteomics supports mitochondrial
      localization, but this is less specific than the mitochondrial outer
      membrane/TOM complex annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
    additional_reference_ids:
    - file:human/TOMM6/TOMM6-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5205661
  review:
    summary: >-
      Reactome places TOMM6 at the mitochondrial outer membrane in TOM/PINK1
      pathway context. This matches the structural TOM core localization.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM6/TOMM6-deep-research-falcon.md
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings:
  - statement: InterPro2GO mapping assigns TOM complex membership to TOMM6 based on
      the Tom6 (IPR029182) / PF15184 family signature.
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
  - statement: PAINT/IBA phylogenetic propagation supports mitochondrial localization
      for TOMM6 across the Tom6 family.
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings:
  - statement: UniProt subcellular location annotation places TOMM6 in the mitochondrial
      outer membrane.
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings:
  - statement: Curated immunofluorescence localization places TOMM6 in mitochondria.
- id: PMID:18331822
  title: Identification of Tom5 and Tom6 in the preprotein translocase complex of
    human mitochondrial outer membrane.
  findings:
  - statement: Human Tom5 and Tom6 were immuno-isolated as associated subunits of
      the TOM preprotein translocase from HeLa cells expressing hTom22-FLAG.
    supporting_text: We immuno-isolated the TOM complex from HeLa cells expressing
      hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together
      with the other components including Tom7.
  - statement: Tom6 is associated with Tom40 in the mammalian TOM complex.
    supporting_text: These small Tom proteins are associated with Tom40 in the TOM
      complex.
  - statement: Small Tom proteins (Tom5/Tom6/Tom7) maintain the structural integrity
      of the human TOM complex, with double knockdown impairing precursor import.
    supporting_text: Matrix import of preprotein was affected by double knockdown
      of any combination of small Tom proteins. These results indicate that human
      small Tom proteins maintain the structural integrity of the TOM complex.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: TOMM6 appears in the high-throughput Y2H-based HuRI binary protein
      interactome map; this is generic protein-binding evidence and does not by itself
      define the specific role of TOMM6 in the TOM core.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings:
  - statement: TOMM6 is included in the high-confidence quantitative human mitochondrial
      proteome supporting mitochondrial localization.
- id: Reactome:R-HSA-5205661
  title: Pink1 is recruited from the cytoplasm to the mitochondria
  findings:
  - statement: Reactome places TOMM6 at the mitochondrial outer membrane as part of
      the TOM complex in the PINK1 recruitment pathway.
- id: file:human/TOMM6/TOMM6-deep-research-falcon.md
  title: Falcon deep research report for human TOMM6
  findings:
  - statement: TOMM6 is an α-helical single-pass outer mitochondrial membrane protein
      that participates in the TOM translocase together with TOMM40 (pore) and TOMM22
      (receptor).
    supporting_text: "Tom6/TOMM6 as an α-helical single-pass outer mitochondrial\
      \ membrane (OMM) protein that participates in the TOM (translocase of the outer\
      \ membrane) protein-import machinery together with TOMM40 (pore) and TOMM22\
      \ (core receptor/adaptor)."
  - statement: TOMM6 functions as an auxiliary structural/regulatory subunit supporting
      assembly, stability, and oligomerization of the TOM core rather than as a stand-alone
      transporter.
    supporting_text: "**TOMM6** is best defined as an **auxiliary structural/regulatory\
      \ subunit** that supports **assembly, stability, and oligomerization** of the\
      \ TOM core rather than directly binding and transporting substrates as a stand-alone\
      \ importer."
  - statement: TOMM6 contacts the Tom40 β-barrel (around β13–β15) primarily via hydrophobic
      interactions and helps anchor TOMM22 to the TOMM40 pore.
    supporting_text: "Tom6 contacts the **Tom40 β-barrel**, especially around\
      \ the **β13–β15** region, primarily via hydrophobic interactions."
  - statement: siRNA targeting of small TOMM proteins (TOMM5/6/7) destabilizes TOM
      complex proteins, consistent with an assembly/stability role.
    supporting_text: siRNA targeting of the small TOMM proteins (TOMM5/6/7) destabilizes
      TOM complex proteins, supporting an assembly/stability role.
  - statement: TOMM6 is positioned on the exterior of the Tom40 β-barrel as a single-pass
      α-helical membrane protein, consistent with an accessory structural role.
    supporting_text: Tom6 as a **single-pass α-helical membrane protein** (single
      transmembrane segment) positioned on the exterior of the Tom40 β-barrel, consistent
      with an accessory structural role.
core_functions:
- description: >-
    TOMM6 is a structural/regulatory small Tom subunit that stabilizes and
    organizes the mitochondrial TOM core, supporting TOMM40/TOMM22-dependent
    mitochondrial protein import and TOM complex assembly.
  supported_by:
  - reference_id: file:human/TOMM6/TOMM6-deep-research-falcon.md
    supporting_text: "In this framework, **TOMM6** is best defined as an **auxiliary structural/regulatory subunit** that supports **assembly, stability, and oligomerization** of the TOM core"
  - reference_id: file:human/TOMM6/TOMM6-deep-research-falcon.md
    supporting_text: "Human TOMM6 is an OMM component of TOM."
  - reference_id: file:human/TOMM6/TOMM6-deep-research-falcon.md
    supporting_text: "TOMM6 is not itself the pore; rather it supports the protein import pathway by maintaining TOM structural integrity and assembly state."
  contributes_to_molecular_function:
    id: GO:0008320
    label: protein transmembrane transporter activity
  directly_involved_in:
  - id: GO:0070096
    label: mitochondrial outer membrane translocase complex assembly
  locations:
  - id: GO:0005741
    label: mitochondrial outer membrane
  in_complex:
    id: GO:0140596
    label: TOM complex
proposed_new_terms: []
suggested_questions:
- question: >-
    Which human TOMM6 surfaces are required for TOMM22 anchoring versus general
    TOMM40 core stabilization?
  experts: []
- question: >-
    Does endogenous TOMM6 depletion preferentially impair assembly of new TOM
    complexes or the import activity of pre-existing TOM complexes?
  experts: []
suggested_experiments:
- hypothesis: >-
    TOMM6 promotes TOM core assembly by stabilizing TOMM40-TOMM22 contacts.
  description: >-
    Introduce TOMM6 point mutants in residues predicted to contact TOMM40 or
    TOMM22, then measure TOM complex assembly by blue-native PAGE/cryo-EM and
    mitochondrial precursor import using endogenous rescue assays.
  experiment_type: structure-guided mutagenesis and import assay

Gene Description

Existing Annotations Review

Core Functions

TOMM6 is a structural/regulatory small Tom subunit that stabilizes and organizes the mitochondrial TOM core, supporting TOMM40/TOMM22-dependent mitochondrial protein import and TOM complex assembly.