TOMM7

GO Term	Evidence	Action	Reason
GO:0005742 mitochondrial outer membrane translocase complex	IBA GO_REF:0000033	ACCEPT	Summary: Correct phylogenetic inference. TOMM7 is a conserved small TOM subunit in the mitochondrial outer membrane translocase complex. Supporting Evidence: file:human/TOMM7/TOMM7-deep-research-falcon.md TOMM7 is an outer mitochondrial membrane subunit of the TOM machinery.
GO:0005741 mitochondrial outer membrane	IEA GO_REF:0000044	ACCEPT	Summary: Correct UniProt-derived localization. TOMM7 is a single-pass outer mitochondrial membrane TOM subunit.
GO:0005742 mitochondrial outer membrane translocase complex	IEA GO_REF:0000002	ACCEPT	Summary: Correct InterPro-derived annotation. TOMM7 is a Tom7-family small TOM complex subunit.
GO:0030150 protein import into mitochondrial matrix	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Correct as a broad TOM pathway consequence but not TOMM7's most specific role. TOMM7 regulates TOM complex assembly/stability and supports import indirectly through the TOM complex. Reason: Matrix import is one route through TOM; TOMM7's core role is TOM complex regulation.
GO:0005515 protein binding	IPI PMID:12198123 Insertion and assembly of human tom7 into the preprotein tra...	REMOVE	Summary: Protein binding is too generic. The relevant result is TOMM7 insertion and assembly into the TOM complex, captured by TOM complex and assembly terms. Reason: Protein binding is uninformative for TOMM7 function.
GO:0005515 protein binding	IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma...	REMOVE	Summary: Histone crosslinking protein binding is not part of the curated TOMM7 mitochondrial outer membrane/TOM function. Reason: Protein binding is uninformative and likely unrelated to TOMM7 core function.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	REMOVE	Summary: Generic OpenCell protein binding does not capture TOMM7's function as a regulatory/structural TOM complex subunit. Reason: Protein binding is uninformative; complex and process annotations are more appropriate.
GO:0030150 protein import into mitochondrial matrix	TAS PMID:15644312 Dissection of the mitochondrial import and assembly pathway ...	KEEP AS NON CORE	Summary: Broad but valid for the TOM import pathway. TOMM7 contributes indirectly through TOM complex organization rather than acting as the matrix-import motor or pore. Reason: Matrix import is a TOM pathway outcome but not TOMM7's most specific function.
GO:0005741 mitochondrial outer membrane	NAS PMID:18331822 Identification of Tom5 and Tom6 in the preprotein translocas...	ACCEPT	Summary: Correct localization. TOMM7 is a small outer mitochondrial membrane subunit of the TOM machinery.
GO:0045040 protein insertion into mitochondrial outer membrane	NAS PMID:18331822 Identification of Tom5 and Tom6 in the preprotein translocas...	MODIFY	Summary: The broad TOM biology is related, but TOMM7 is not an independent insertase. The specific supported role is TOM complex assembly/stability and oligomeric-state regulation. Reason: Replace outer membrane insertion with TOM complex assembly/stability. 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 and specific. TOMM7 is a TOM core/holo complex subunit adjacent to TOM40/TOM22 and the other small Tom proteins.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	MARK AS OVER ANNOTATED	Summary: Correct but too general. TOMM7 is specifically a mitochondrial outer membrane TOM complex subunit. Reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
GO:0005742 mitochondrial outer membrane translocase complex	TAS PMID:24270810 High-content genome-wide RNAi screens identify regulators of...	ACCEPT	Summary: Accepted. The TOMM7/PINK1-Parkin evidence is consistent with TOMM7 acting at the TOM complex.
GO:0031647 regulation of protein stability	IMP PMID:24270810 High-content genome-wide RNAi screens identify regulators of...	ACCEPT	Summary: Accepted for the PINK1 context. TOMM7 is required for efficient PINK1 stabilization/activation at the TOM complex after mitochondrial depolarization.
GO:1903749 positive regulation of protein localization to mitochondrion	IMP PMID:24270810 High-content genome-wide RNAi screens identify regulators of...	ACCEPT	Summary: Accepted as a PINK1-related annotation. TOMM7 supports PINK1 accumulation at damaged mitochondria/TOM after depolarization.
GO:1905091 positive regulation of type 2 mitophagy	IMP PMID:24270810 High-content genome-wide RNAi screens identify regulators of...	ACCEPT	Summary: Accepted. TOMM7 enables PINK1 stabilization/activation at TOM and downstream Parkin recruitment, supporting PINK1-Parkin mitophagy signaling.
GO:0005741 mitochondrial outer membrane	TAS Reactome:R-HSA-5205661	ACCEPT	Summary: Accepted. Reactome places TOMM7 at the mitochondrial outer membrane in TOM/PINK1 pathway context.
GO:0005739 mitochondrion	IDA PMID:12198123 Insertion and assembly of human tom7 into the preprotein tra...	MARK AS OVER ANNOTATED	Summary: Correct but too general. TOMM7 is specifically an outer membrane TOM complex subunit. Reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
GO:0005742 mitochondrial outer membrane translocase complex	IDA PMID:12198123 Insertion and assembly of human tom7 into the preprotein tra...	ACCEPT	Summary: Accepted. PMID:12198123 directly addresses insertion and assembly of human TOM7 into the TOM complex.
GO:0008320 protein transmembrane transporter activity	TAS PMID:15644312 Dissection of the mitochondrial import and assembly pathway ...	REMOVE	Summary: TOMM7 is not the TOM protein-conducting pore. Its role is regulatory and structural within the TOM complex rather than direct transporter activity. Reason: TOMM7 regulates TOM complex assembly/stability but does not independently enable protein transmembrane transporter activity.

Deep Research

Falcon

(TOMM7-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 36 citations 2026-05-11T12:29:42.246057

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Research report: Human TOMM7 (UniProt Q9P0U1) — functional annotation, mechanisms, and recent findings

0) Target identity verification (mandatory)

The UniProt accession Q9P0U1 corresponds to Homo sapiens TOMM7 (synonyms: TOM7, TOMM07), annotated as “mitochondrial import receptor subunit TOM7 homolog”, a small Tom7-family component of the translocase of the outer mitochondrial membrane (TOM) complex. The retrieved human structural, mechanistic, and genetics literature consistently uses TOMM7/Tom7 to describe this TOM complex subunit and does not indicate an alternative gene/protein identity under this symbol in humans (pitt2021abiochemicaland pages 16-17, raimi2024mechanismofhuman pages 1-2, young2023ahypomorphicvariant pages 1-2).

1) Key concepts and definitions (current understanding)

1.1 The TOM complex and TOMM7’s functional class

The TOM complex is the major entry gate for nuclear-encoded mitochondrial precursor proteins, consisting of the pore-forming TOM40 plus receptor and accessory subunits. In humans, one commonly described composition includes seven subunits: TOM5, TOM6, TOM7, TOM20, TOM22, TOM40, TOM70 (raimi2024mechanismofhuman pages 1-2, su2024structureofthe pages 1-3). In human cryo-EM structures, TOMM7 is a small, single-pass α-helical subunit that associates peripherally with the TOM40 β-barrel and is part of the TOM core complex (wang2020atomicstructureof pages 1-2, pitt2021abiochemicaland pages 6-9).

Functionally, TOMM7 is best classified as a non-enzymatic regulatory/structural subunit: it does not form the transport pore itself but instead modulates TOM complex assembly, stability, and higher-order organization, and it contributes to mitochondrial quality-control signaling (pitt2021abiochemicaland pages 6-9, su2024structureofthe pages 1-3).

1.2 Localization and topology

TOMM7 is an outer mitochondrial membrane subunit of the TOM machinery. Topology evidence summarized in a structural/biochemical review indicates that TOMM7’s C-terminus faces the intermembrane space (IMS): fusing GFP to the IMS-facing C-terminus abolishes correct mitochondrial targeting, consistent with an IMS-exposed C-terminal region (pitt2021abiochemicaland pages 16-17).

1.3 Structural features relevant to mechanism

Recent structural syntheses emphasize that human Tom7 has an IMS-directed extended/elongated C-terminal segment/loop (nussberger2024newinsightsinto pages 2-4). Cryo-EM-based reviews also describe an extended IMS segment in human Tom7 containing a negatively charged patch (pitt2021abiochemicaland pages 11-12). In addition, Tom7’s transmembrane helix shows a kink/bend, positioning it near Tom22/Tom40 interfaces and supporting a role in organizing TOM subunit architecture and oligomeric state (pitt2021abiochemicaland pages 6-9).

2) TOMM7 primary functions and supported mechanisms

2.1 Regulator of TOM complex assembly, stability, and oligomeric state

Human TOM structures show Tom7 as one of the small subunits surrounding TOM40 in the TOM core, consistent with a stabilizing/organizing role within the complex (wang2020atomicstructureof pages 1-2, pitt2021abiochemicaland pages 6-9). Functional interpretations from cryo-EM and biochemical literature support that Tom7 modulates assembly dynamics and can function antagonistically to Tom6: Tom6 promotes TOM formation/stability, whereas Tom7 delays assembly and/or reduces stability (wang2020atomicstructureof pages 1-2, su2024structureofthe pages 1-3). A 2024 cryo-EM study of the human TOM holo complex (capturing intact Tom20) explicitly states that Tom6 stabilizes TOM via interaction with Tom22, while Tom7 reduces complex stability (su2024structureofthe pages 1-3).

Together, these data support annotating TOMM7 as a regulatory subunit influencing TOM stability and higher-order organization rather than as a canonical receptor (TOM20/TOM70) or the pore (TOM40) (su2024structureofthe pages 1-3, raimi2024mechanismofhuman pages 1-2).

2.2 Role in PINK1 import arrest and PINK1/Parkin mitophagy signaling

A major mechanistic role of TOMM7 in mammalian cells is its requirement for PINK1 stabilization/activation at the TOM complex on damaged mitochondria.

Genetic/functional evidence (cell biology): Tom7 was identified as essential for PINK1 accumulation on the outer mitochondrial membrane (OMM) after loss of mitochondrial membrane potential; without Tom7, PINK1 is imported into depolarized mitochondria and then cleaved by OMA1 rather than accumulating for Parkin activation (sekine2019reciprocalrolesof pages 1-3). This supports a model in which TOMM7 promotes or enables import arrest of PINK1 at TOM under depolarization conditions.
Mechanistic reconstitution (2024): In a reconstituted system, co-expression of human PINK1 together with all seven TOM subunits is sufficient for PINK1 activation. The study demonstrates an essential role for TOM40 and its structurally associated TOM7 and TOM22 in PINK1 activation, while TOM20 and TOM70 are required for optimal activation (raimi2024mechanismofhuman pages 1-2). This work also provides a quantitative biochemical signature: under depolarization, full-length PINK1 appears in a distinct ~700-kDa TOM-associated complex, compared with native TOM at ~500 kDa by BN-PAGE (raimi2024mechanismofhuman pages 1-2).
Downstream effect on Parkin: A structural/biochemical review summarizes evidence that human Tom7 is critical for Parkin recruitment/OMM accumulation and PINK1 accumulation after depolarization, and notes that defects in Tom7-deficient cells can be rescued by OMA1 knockdown in some contexts, indicating functional interplay between TOMM7-dependent PINK1 stabilization and proteolytic regulation by OMA1 (pitt2021abiochemicaland pages 16-17, pitt2021abiochemicaland pages 17-19).

Collectively, the most defensible functional annotation is that TOMM7 is a TOM-core accessory subunit that links outer-membrane protein import machinery to mitochondrial quality control by enabling PINK1 retention/activation at TOM during stress, thereby promoting PINK1–Parkin mitophagy signaling (sekine2019reciprocalrolesof pages 1-3, raimi2024mechanismofhuman pages 1-2).

3) Recent developments and latest research (prioritizing 2023–2024)

3.1 2024 structural insights into TOMM7 topology and dynamics

A 2024 structural review highlights Tom7’s elongated IMS-oriented C-terminus/loop, proposing that this element may help shape the IMS-side exit pathway of the TOM pore region in human complexes (nussberger2024newinsightsinto pages 2-4). In parallel, 2024 cryo-EM work capturing the TOM holo complex (including intact Tom20) reinforces Tom7’s presence as a small subunit surrounding Tom40 and frames Tom7 as a destabilizing counterbalance to Tom6 stabilization (su2024structureofthe pages 1-3). These studies are important because they shift TOMM7 annotation from a generic “small TOM subunit” to a structurally distinctive, IMS-featured modulator of TOM architecture (nussberger2024newinsightsinto pages 2-4, pitt2021abiochemicaland pages 11-12).

3.2 2024 mechanistic clarification of TOM subunit requirements for PINK1 activation

The 2024 Science Advances reconstitution study is a key advance because it disentangles TOM subunit contributions: TOM7 (with TOM40 and TOM22) is essential, whereas receptor subunits TOM20/TOM70 are required for optimal activation, and the work explicitly frames these insights as enabling development of small-molecule PINK1 activators as a Parkinson’s disease therapeutic strategy (raimi2024mechanismofhuman pages 1-2).

3.3 2023–2024 human genetics: TOMM7 as a Mendelian disease gene

Two recent clinical genetics reports provide strong real-world evidence that TOMM7 dysfunction causes multisystem developmental disease:

2023 (Jan): p.Trp25Arg (W25R) hypomorphic allele. A homozygous missense variant c.73T>C (p.Trp25Arg) causes syndromic short stature and developmental delay with skeletal dysplasia, hypotonia, microvesicular liver steatosis, and ocular findings; mouse modeling supports the allele as hypomorphic and associates TOMM7 perturbation with bioenergetic uncoupling-like phenotypes (young2023ahypomorphicvariant pages 1-2). URL: https://doi.org/10.1016/j.xhgg.2022.100148 (Jan 2023) (young2023ahypomorphicvariant pages 1-2).
2024 (Dec): recurrent p.Pro29Leu (P29L) expands phenotype to moyamoya. A recurrent homozygous p.Pro29Leu (p.P29L; c.86C>T) was found in 9 patients from 7 unrelated families with microcephaly, short stature/postnatal growth failure, developmental delay, facial dysmorphism, atrophic macular scarring, and moyamoya disease in 5/9 (li2024homozygousvariantin pages 2-3). This association reached genome-wide significance (P = 2.5072 × 10−23) in the authors’ analysis, and the paper reports a TOMM7 frequency across gnomAD ancestry groups of 0.0251% (li2024homozygousvariantin pages 14-16). URL: https://doi.org/10.1016/j.ebiom.2024.105476 (Dec 2024) (li2024homozygousvariantin pages 2-3, li2024homozygousvariantin pages 14-16).

These findings support including TOMM7 in diagnostic gene panels for syndromic growth failure/microcephaly and potentially for pediatric cerebrovascular syndromes with mitochondrial features (li2024homozygousvariantin pages 2-3, young2023ahypomorphicvariant pages 1-2).

4) Pathways, interactions, and cellular contexts

4.1 Core pathway: mitochondrial protein import via TOM

TOMM7 participates in mitochondrial protein import indirectly by regulating the integrity and assembly state of the TOM complex, which is required for the import of most nuclear-encoded mitochondrial proteins (raimi2024mechanismofhuman pages 1-2, su2024structureofthe pages 1-3). Thus, TOMM7 is best placed in pathways annotated as mitochondrial protein targeting/import and mitochondrial outer membrane translocation.

4.2 Mitochondrial quality control: PINK1–Parkin pathway

When mitochondria lose membrane potential, PINK1 is stabilized at the TOM complex and triggers Parkin recruitment/activation to initiate mitophagy. TOMM7 is a key determinant of this switch: loss of Tom7 prevents PINK1 arrest at the OMM and leads to OMA1-dependent cleavage, thereby reducing PINK1’s ability to activate Parkin on damaged mitochondria (sekine2019reciprocalrolesof pages 1-3). Reconstitution work places TOMM7 among the essential TOM components for PINK1 activation (raimi2024mechanismofhuman pages 1-2).

5) Quantitative data and key statistics from recent studies

BN-PAGE complex sizes (2024 mechanistic study): full-length PINK1 stabilizes in a TOM-associated complex at ~700 kDa, distinct from native TOM at ~500 kDa (raimi2024mechanismofhuman pages 1-2).
Population/statistical genetics (2024): p.P29L cohort of 9 patients / 7 families; moyamoya in 5/9; association significance P = 2.5072 × 10−23; reported gnomAD presence 0.0251% across ancestry groups (li2024homozygousvariantin pages 2-3, li2024homozygousvariantin pages 14-16).
Mitochondrial proteomics/flux (2022, still highly relevant to 2024 genetics): in TOMM7 p.P29L patient fibroblasts, mitochondrial proteomics detected 587 proteins, with 91 differentially expressed (P<0.05), and patient fibroblasts showed elevated basal and maximal OCR (garg2022autosomalrecessiveprogeroid pages 2-3). Variant functional assays show reduced TOMM7 interaction with TOMM40 and TOMM22 (garg2022autosomalrecessiveprogeroid pages 3-5).

These numbers support the interpretation that TOMM7 variants can shift mitochondrial import/proteome balance and bioenergetics without necessarily collapsing mitochondrial respiration globally (garg2022autosomalrecessiveprogeroid pages 2-3, garg2022autosomalrecessiveprogeroid pages 3-5).

6) Current applications and real-world implementations

Clinical genetics / diagnostics (2023–2024 implementation): TOMM7 has clear relevance as a Mendelian disease gene for syndromic growth and neurodevelopmental phenotypes, and (in 2024) a distinct syndrome including moyamoya. These data motivate TOMM7 inclusion in diagnostic pipelines for microcephaly + growth failure + developmental delay, particularly when accompanied by ophthalmologic findings and/or cerebrovascular disease (li2024homozygousvariantin pages 2-3, young2023ahypomorphicvariant pages 1-2).
Therapeutic strategy development (mitophagy modulation): mechanistic reconstitution of PINK1 activation at TOM explicitly frames the work as enabling small-molecule activators of PINK1 as a therapeutic approach for Parkinson’s disease, and identifies TOM7/TOM22/TOM40 as essential components to consider in such strategies (raimi2024mechanismofhuman pages 1-2). Complementarily, earlier mechanistic work suggests that modulating OMA1 can rescue Parkin recruitment for some PINK1 dysfunction contexts, highlighting the TOMM7–OMA1 axis as a conceptual intervention point (sekine2019reciprocalrolesof pages 1-3, pitt2021abiochemicaland pages 17-19).

7) Expert synthesis and interpretation (authoritative sources)

Structural/biochemical reviews emphasize that the TOM complex is not only a constitutive import machine but also a hub connecting import, mitochondrial homeostasis, and disease processes. Within that framework, TOMM7 is increasingly viewed as a regulatory element whose IMS-facing structural features and impact on complex stability can influence both import and quality-control signaling (nussberger2024newinsightsinto pages 2-4, su2024structureofthe pages 1-3). In Parkinson’s-related mechanisms, primary and reconstitution studies converge on TOMM7 as a component required for appropriate PINK1 behavior at the import gate during mitochondrial damage, which helps explain why TOM machinery components are repeatedly implicated in mitophagy regulation and disease-relevant stress responses (sekine2019reciprocalrolesof pages 1-3, raimi2024mechanismofhuman pages 1-2).

8) Consolidated evidence table

Topic	Key findings	Evidence type	Publication (first author, year, journal)	Publication date (month/year if available)	URL	Notes for functional annotation
Identity/localization/topology	TOMM7 matches UniProt Q9P0U1: a small human TOM complex subunit in the Tom7 family. It is part of the TOM core/holo complex with TOM40, TOM22, TOM5, TOM6, and receptors TOM20/TOM70. Topology data support a single-pass outer-membrane helix with the C-terminus facing the intermembrane space (IMS); GFP fusion to the C-terminus disrupts targeting, consistent with an IMS-exposed tail. (pitt2021abiochemicaland pages 16-17, raimi2024mechanismofhuman pages 1-2, pitt2021abiochemicaland pages 3-6)	Cryo-EM, cell biology, review	Pitt, 2021, Cells; Raimi, 2024, Science Advances	05/2021; 06/2024	https://doi.org/10.3390/cells10051164 ; https://doi.org/10.1126/sciadv.adn7191	Annotate as a non-enzymatic regulatory/structural TOM subunit of the mitochondrial outer membrane, not a transporter channel itself.
Structural features	Human Tom7 has a kinked transmembrane helix and an elongated C-terminal/loop segment projecting toward the IMS; this IMS-directed segment is described as extended and includes a negatively charged patch. Tom7 lies peripherally adjacent to the Tom40 β-barrel and near Tom22/Tom5, helping shape the TOM core architecture. (nussberger2024newinsightsinto pages 2-4, pitt2021abiochemicaland pages 6-9, pitt2021abiochemicaland pages 11-12)	Cryo-EM, structural review	Nussberger, 2024, Biochemical Society Transactions; Pitt, 2021, Cells	04/2024; 05/2021	https://doi.org/10.1042/bst20231236 ; https://doi.org/10.3390/cells10051164	Useful for annotation of topology and likely IMS-side regulatory interactions during precursor exit/complex organization.
TOM assembly & stability	Tom7 is a small α-helical TOM subunit that surrounds Tom40 and participates in assembly/stability dynamics. Human and comparative studies support an antagonistic relationship with Tom6: Tom6 stabilizes TOM, whereas Tom7 can reduce stability/delay assembly; loss of Tom7 increases tetramer formation and increases hTom40 import/biogenesis in some systems. (wang2020atomicstructureof pages 1-2, pitt2021abiochemicaland pages 6-9, su2024structureofthe pages 1-3)	Cryo-EM, biochemical genetics, review	Wang, 2020, Cell Discovery; Pitt, 2021, Cells; Su, 2024, PNAS Nexus	09/2020; 05/2021; 06/2024	https://doi.org/10.1038/s41421-020-00198-2 ; https://doi.org/10.3390/cells10051164 ; https://doi.org/10.1093/pnasnexus/pgae269	Best described as a regulator of TOM complex biogenesis/oligomeric state rather than a core receptor or pore-forming unit.
PINK1/Parkin mitophagy	TOMM7 is required for efficient PINK1 stabilization/activation at damaged mitochondria and for downstream Parkin recruitment. In TOMM7-deficient cells, PINK1 fails to accumulate after depolarization; Tom7 loss allows PINK1 import/OMA1 cleavage instead of OMM arrest. OMA1 knockdown can rescue defects in some contexts. Reconstituted human TOM studies show TOM40, TOM22, and TOM7 are essential for PINK1 activation, while TOM20/TOM70 optimize activation. BN-PAGE detects full-length PINK1 in a ~700-kDa TOM-associated complex versus native TOM at ~500-kDa. (pitt2021abiochemicaland pages 16-17, raimi2024mechanismofhuman pages 1-2, sekine2019reciprocalrolesof pages 1-3, pitt2021abiochemicaland pages 17-19)	Cell biology, reconstitution, BN-PAGE	Sekine, 2019, Molecular Cell; Raimi, 2024, Science Advances; Pitt, 2021, Cells	03/2019; 06/2024; 05/2021	https://doi.org/10.1016/j.molcel.2019.01.002 ; https://doi.org/10.1126/sciadv.adn7191 ; https://doi.org/10.3390/cells10051164	Functional annotation should mention a role in mitochondrial quality control/mitophagy via PINK1 import arrest and activation at TOM.
Human disease genetics	Hypomorphic TOMM7 p.Trp25Arg (c.73T>C; p.W25R) causes syndromic short stature/developmental delay with skeletal dysplasia, hypotonia, liver steatosis, and ocular findings; proband homozygous, parents heterozygous. Prior structural interpretation places Trp25 near Arg24, predicted to affect TOMM40 interaction. (young2023ahypomorphicvariant pages 1-2)	Human genetics, mouse modeling, bioenergetics	Young, 2023, Human Genetics and Genomics Advances	01/2023	https://doi.org/10.1016/j.xhgg.2022.100148	Supports disease relevance of partial TOMM7 loss of function and TOM complex dysregulation in growth/development.
Human disease genetics	TOMM7 p.Pro29Leu (c.86C>T; p.P29L) was first linked to autosomal recessive progeroid syndrome/Garg-Mishra phenotype in a single family: severe dwarfism, mandibular hypoplasia, hyperopia/micro-ophthalmia, partial lipodystrophy. The variant is rare in gnomAD (MAF 0.000048 in East Asians in one report) and affects a fully conserved residue in the kinked helix contacting TOMM40. (garg2022autosomalrecessiveprogeroid pages 1-2, garg2022autosomalrecessiveprogeroid pages 2-3, garg2022autosomalrecessiveprogeroid pages 3-5)	Human genetics, structural interpretation, proteomics	Garg, 2022, Journal of Clinical Investigation	12/2022	https://doi.org/10.1172/jci156864	Strong evidence that altered TOMM7-TOM interactions can produce a multisystem developmental/progeroid disorder.
Human disease genetics	A 2024 study expanded p.Pro29Leu to a recurrent disease allele: homozygous TOMM7 p.P29L in 9 patients from 7 unrelated families, with postnatal growth failure/short stature, microcephaly, facial dysmorphism, developmental delay, atrophic macular scarring, and moyamoya disease in 5/9 patients. Association reached genome-wide significance (P = 2.5072 × 10^-23). The variant frequency quoted across gnomAD ancestry groups was 0.0251%, and the paper notes enrichment in the Taiwanese population. (li2024homozygousvariantin pages 2-3, li2024homozygousvariantin pages 1-2, li2024homozygousvariantin pages 14-16)	Human genetics, population analysis, iPSC/endothelial biology	Li, 2024, eBioMedicine	12/2024	https://doi.org/10.1016/j.ebiom.2024.105476	Expands annotation to include cerebrovascular disease susceptibility and metabolic reprogramming phenotypes.
Quantitative data/stats	In TOMM7 p.P29L patient fibroblasts, mitochondrial proteomics detected 587 proteins, with 91 differentially expressed proteins (P<0.05); GSEA showed enrichment of ATP-production/proton-transport proteins and reduction of phospholipid metabolic proteins. Patient fibroblasts showed elevated basal and maximal OCR. (garg2022autosomalrecessiveprogeroid pages 2-3, garg2022autosomalrecessiveprogeroid pages 3-5)	Proteomics, extracellular flux	Garg, 2022, Journal of Clinical Investigation	12/2022	https://doi.org/10.1172/jci156864	Quantitative support that TOMM7 perturbs select mitochondrial proteome/import balance rather than abolishing respiration globally.
Quantitative data/stats	p.W25R and Tomm7 deficiency produce a paradoxical bioenergetic phenotype: increased oxygen consumption despite bioenergetic deficiency, interpreted as uncoupling between oxidation and ATP synthesis rather than overt TCA/ETC failure. In 2024 endothelial/iPSC models with p.P29L, respiration was slightly decreased while glycolytic ATP production increased significantly, with elevated hexokinase 2 and enhanced glycolysis. (young2023ahypomorphicvariant pages 1-2, li2024homozygousvariantin pages 1-2)	Mouse/cell physiology, iPSC metabolism	Young, 2023, HGGA; Li, 2024, eBioMedicine	01/2023; 12/2024	https://doi.org/10.1016/j.xhgg.2022.100148 ; https://doi.org/10.1016/j.ebiom.2024.105476	Suggests TOMM7 loss/hypomorphism alters mitochondrial import-linked metabolic setpoints and can trigger glycolytic compensation.
Human disease genetics / mechanism	TOMM7 p.P29L retains mitochondrial localization but shows reduced interaction with TOMM40 and TOMM22, consistent with impaired integration into or regulation of the TOM complex. In contrast, Parkin-dependent mitophagy appeared largely intact in patient fibroblasts in the JCI study, indicating that not all TOMM7 disease alleles phenocopy complete TOMM7 loss for mitophagy. (garg2022autosomalrecessiveprogeroid pages 2-3, garg2022autosomalrecessiveprogeroid pages 5-6, garg2022autosomalrecessiveprogeroid pages 3-5)	Co-IP, localization, mitophagy assay	Garg, 2022, Journal of Clinical Investigation	12/2022	https://doi.org/10.1172/jci156864	Important nuance: disease mechanism may involve selective defects in TOM assembly/import specificity rather than total mitophagy failure.
Functional systems biology	In vascular/endothelial contexts, TOMM7 modulates mitochondrial Rac1/redox signaling and cerebrovascular network formation; Tomm7 loss in zebrafish and mice causes cerebrovascular abnormalities. The 2024 human p.P29L study connects this biology to moyamoya disease and endothelial tube-formation defects in edited iPSC-derived endothelial cells. (li2024homozygousvariantin pages 2-3, li2024homozygousvariantin pages 1-2)	Animal models, endothelial cell biology, iPSC	Li, 2024, eBioMedicine	12/2024	https://doi.org/10.1016/j.ebiom.2024.105476	Real-world relevance includes developmental vascular pathology, not only mitochondrial import biochemistry.

Table: This table summarizes identity, structural biology, mitochondrial import function, mitophagy roles, and disease genetics for human TOMM7 (UniProt Q9P0U1). It consolidates recent and foundational evidence, including variant-specific clinical findings and key quantitative results useful for functional annotation.

9) Summary functional annotation (actionable)

TOMM7 (Tom7) is a small, single-pass outer mitochondrial membrane TOM complex subunit with an IMS-facing extended C-terminal/loop segment and a kinked transmembrane helix (nussberger2024newinsightsinto pages 2-4, pitt2021abiochemicaland pages 11-12). Its primary role is to regulate TOM complex assembly/oligomeric state and stability, acting in opposition to Tom6 in stability control, and to support the TOM complex’s function as a signaling node in mitochondrial quality control (su2024structureofthe pages 1-3, pitt2021abiochemicaland pages 6-9). TOMM7 is also required for efficient PINK1 stabilization/activation at the TOM complex under mitochondrial depolarization, thereby enabling Parkin recruitment and PINK1–Parkin mitophagy (sekine2019reciprocalrolesof pages 1-3, raimi2024mechanismofhuman pages 1-2). Human biallelic missense variants (notably p.W25R and p.P29L) cause syndromic developmental disease, and recurrent p.P29L is associated with a microcephalic osteodysplastic dwarfism syndrome frequently complicated by moyamoya disease (young2023ahypomorphicvariant pages 1-2, li2024homozygousvariantin pages 2-3).

References

(pitt2021abiochemicaland pages 16-17): Ashley S. Pitt and Susan K. Buchanan. A biochemical and structural understanding of tom complex interactions and implications for human health and disease. Cells, 10:1164, May 2021. URL: https://doi.org/10.3390/cells10051164, doi:10.3390/cells10051164. This article has 46 citations.
(raimi2024mechanismofhuman pages 1-2): Olawale G. Raimi, Hina Ojha, Kenneth Ehses, Verena Dederer, Sven M. Lange, Cristian Polo Rivera, Tom D. Deegan, Yinchen Chen, Melanie Wightman, Rachel Toth, Karim P. M. Labib, Sebastian Mathea, Neil Ranson, Rubén Fernández-Busnadiego, and Miratul M. K. Muqit. Mechanism of human pink1 activation at the tom complex in a reconstituted system. Science Advances, Jun 2024. URL: https://doi.org/10.1126/sciadv.adn7191, doi:10.1126/sciadv.adn7191. This article has 40 citations and is from a highest quality peer-reviewed journal.
(young2023ahypomorphicvariant pages 1-2): Cameron Young, Dominyka Batkovskyte, Miyuki Kitamura, Maria Shvedova, Yutaro Mihara, Jun Akiba, Wen Zhou, Anna Hammarsjö, Gen Nishimura, Shuichi Yatsuga, Giedre Grigelioniene, and Tatsuya Kobayashi. A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit tomm7 causes short stature and developmental delay. Human Genetics and Genomics Advances, 4:100148, Jan 2023. URL: https://doi.org/10.1016/j.xhgg.2022.100148, doi:10.1016/j.xhgg.2022.100148. This article has 23 citations and is from a peer-reviewed journal.
(su2024structureofthe pages 1-3): Jiayue Su, Xuyang Tian, Ziyi Wang, Jiawen Yang, Shan Sun, and Sen-Fang Sui. Structure of the intact tom20 receptor in the human translocase of the outer membrane complex. PNAS Nexus, Jun 2024. URL: https://doi.org/10.1093/pnasnexus/pgae269, doi:10.1093/pnasnexus/pgae269. This article has 12 citations and is from a peer-reviewed journal.
(wang2020atomicstructureof pages 1-2): Wenhe Wang, Xudong Chen, Laixing Zhang, Jingbo Yi, Qingxi Ma, Jian Yin, Wei Zhuo, Jinke Gu, and Maojun Yang. Atomic structure of human tom core complex. Cell Discovery, Sep 2020. URL: https://doi.org/10.1038/s41421-020-00198-2, doi:10.1038/s41421-020-00198-2. This article has 151 citations and is from a peer-reviewed journal.
(pitt2021abiochemicaland pages 6-9): Ashley S. Pitt and Susan K. Buchanan. A biochemical and structural understanding of tom complex interactions and implications for human health and disease. Cells, 10:1164, May 2021. URL: https://doi.org/10.3390/cells10051164, doi:10.3390/cells10051164. This article has 46 citations.
(nussberger2024newinsightsinto pages 2-4): Stephan Nussberger, Robin Ghosh, and Shuo Wang. New insights into the structure and dynamics of the tom complex in mitochondria. Biochemical Society Transactions, 52:911-922, Apr 2024. URL: https://doi.org/10.1042/bst20231236, doi:10.1042/bst20231236. This article has 5 citations and is from a peer-reviewed journal.
(pitt2021abiochemicaland pages 11-12): Ashley S. Pitt and Susan K. Buchanan. A biochemical and structural understanding of tom complex interactions and implications for human health and disease. Cells, 10:1164, May 2021. URL: https://doi.org/10.3390/cells10051164, doi:10.3390/cells10051164. This article has 46 citations.
(sekine2019reciprocalrolesof pages 1-3): Shiori Sekine, Chunxin Wang, Dionisia P. Sideris, Eric Bunker, Zhe Zhang, and Richard J. Youle. Reciprocal roles of tom7 and oma1 during mitochondrial import and activation of pink1. Molecular cell, 73 5:1028-1043.e5, Mar 2019. URL: https://doi.org/10.1016/j.molcel.2019.01.002, doi:10.1016/j.molcel.2019.01.002. This article has 189 citations and is from a highest quality peer-reviewed journal.
(pitt2021abiochemicaland pages 17-19): Ashley S. Pitt and Susan K. Buchanan. A biochemical and structural understanding of tom complex interactions and implications for human health and disease. Cells, 10:1164, May 2021. URL: https://doi.org/10.3390/cells10051164, doi:10.3390/cells10051164. This article has 46 citations.
(li2024homozygousvariantin pages 2-3): Chia-Yi Li, Li-Wen Chen, Meng-Che Tsai, Yen-Yin Chou, Pei-Xuan Lin, Yu-Ming Chang, Wuh-Liang Hwu, Yin-Hsiu Chien, Ju-Li Lin, Hui-An Chen, Ni-Chung Lee, Pen-Hua Su, Tzung-Chien Hsieh, Hannah Klinkhammer, Yi-Chieh Wang, Yi-Ting Huang, Peter M. Krawitz, Sheng-Hsiang Lin, Lynn L.H. Huang, Po-Min Chiang, Min-Hsiu Shih, and Peng-Chieh Chen. Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease. eBioMedicine, 110:105476, Dec 2024. URL: https://doi.org/10.1016/j.ebiom.2024.105476, doi:10.1016/j.ebiom.2024.105476. This article has 7 citations and is from a peer-reviewed journal.
(li2024homozygousvariantin pages 14-16): Chia-Yi Li, Li-Wen Chen, Meng-Che Tsai, Yen-Yin Chou, Pei-Xuan Lin, Yu-Ming Chang, Wuh-Liang Hwu, Yin-Hsiu Chien, Ju-Li Lin, Hui-An Chen, Ni-Chung Lee, Pen-Hua Su, Tzung-Chien Hsieh, Hannah Klinkhammer, Yi-Chieh Wang, Yi-Ting Huang, Peter M. Krawitz, Sheng-Hsiang Lin, Lynn L.H. Huang, Po-Min Chiang, Min-Hsiu Shih, and Peng-Chieh Chen. Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease. eBioMedicine, 110:105476, Dec 2024. URL: https://doi.org/10.1016/j.ebiom.2024.105476, doi:10.1016/j.ebiom.2024.105476. This article has 7 citations and is from a peer-reviewed journal.
(garg2022autosomalrecessiveprogeroid pages 2-3): Abhimanyu Garg, Wee-Teik Keng, Zhenkang Chen, Adwait Amod Sathe, Chao Xing, Pavithira Devi Kailasam, Yanqiu Shao, Nicholas P. Lesner, Claire B. Llamas, Anil K. Agarwal, and Prashant Mishra. Autosomal recessive progeroid syndrome due to homozygosity for a tomm7 variant. Journal of Clinical Investigation, Dec 2022. URL: https://doi.org/10.1172/jci156864, doi:10.1172/jci156864. This article has 33 citations and is from a highest quality peer-reviewed journal.
(garg2022autosomalrecessiveprogeroid pages 3-5): Abhimanyu Garg, Wee-Teik Keng, Zhenkang Chen, Adwait Amod Sathe, Chao Xing, Pavithira Devi Kailasam, Yanqiu Shao, Nicholas P. Lesner, Claire B. Llamas, Anil K. Agarwal, and Prashant Mishra. Autosomal recessive progeroid syndrome due to homozygosity for a tomm7 variant. Journal of Clinical Investigation, Dec 2022. URL: https://doi.org/10.1172/jci156864, doi:10.1172/jci156864. This article has 33 citations and is from a highest quality peer-reviewed journal.
(pitt2021abiochemicaland pages 3-6): Ashley S. Pitt and Susan K. Buchanan. A biochemical and structural understanding of tom complex interactions and implications for human health and disease. Cells, 10:1164, May 2021. URL: https://doi.org/10.3390/cells10051164, doi:10.3390/cells10051164. This article has 46 citations.
(garg2022autosomalrecessiveprogeroid pages 1-2): Abhimanyu Garg, Wee-Teik Keng, Zhenkang Chen, Adwait Amod Sathe, Chao Xing, Pavithira Devi Kailasam, Yanqiu Shao, Nicholas P. Lesner, Claire B. Llamas, Anil K. Agarwal, and Prashant Mishra. Autosomal recessive progeroid syndrome due to homozygosity for a tomm7 variant. Journal of Clinical Investigation, Dec 2022. URL: https://doi.org/10.1172/jci156864, doi:10.1172/jci156864. This article has 33 citations and is from a highest quality peer-reviewed journal.
(li2024homozygousvariantin pages 1-2): Chia-Yi Li, Li-Wen Chen, Meng-Che Tsai, Yen-Yin Chou, Pei-Xuan Lin, Yu-Ming Chang, Wuh-Liang Hwu, Yin-Hsiu Chien, Ju-Li Lin, Hui-An Chen, Ni-Chung Lee, Pen-Hua Su, Tzung-Chien Hsieh, Hannah Klinkhammer, Yi-Chieh Wang, Yi-Ting Huang, Peter M. Krawitz, Sheng-Hsiang Lin, Lynn L.H. Huang, Po-Min Chiang, Min-Hsiu Shih, and Peng-Chieh Chen. Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease. eBioMedicine, 110:105476, Dec 2024. URL: https://doi.org/10.1016/j.ebiom.2024.105476, doi:10.1016/j.ebiom.2024.105476. This article has 7 citations and is from a peer-reviewed journal.
(garg2022autosomalrecessiveprogeroid pages 5-6): Abhimanyu Garg, Wee-Teik Keng, Zhenkang Chen, Adwait Amod Sathe, Chao Xing, Pavithira Devi Kailasam, Yanqiu Shao, Nicholas P. Lesner, Claire B. Llamas, Anil K. Agarwal, and Prashant Mishra. Autosomal recessive progeroid syndrome due to homozygosity for a tomm7 variant. Journal of Clinical Investigation, Dec 2022. URL: https://doi.org/10.1172/jci156864, doi:10.1172/jci156864. This article has 33 citations and is from a highest quality peer-reviewed journal.

Citations

pitt2021abiochemicaland pages 16-17
nussberger2024newinsightsinto pages 2-4
pitt2021abiochemicaland pages 11-12
pitt2021abiochemicaland pages 6-9
su2024structureofthe pages 1-3
sekine2019reciprocalrolesof pages 1-3
raimi2024mechanismofhuman pages 1-2
young2023ahypomorphicvariant pages 1-2
li2024homozygousvariantin pages 2-3
li2024homozygousvariantin pages 14-16
garg2022autosomalrecessiveprogeroid pages 2-3
garg2022autosomalrecessiveprogeroid pages 3-5
wang2020atomicstructureof pages 1-2
pitt2021abiochemicaland pages 17-19
pitt2021abiochemicaland pages 3-6
garg2022autosomalrecessiveprogeroid pages 1-2
li2024homozygousvariantin pages 1-2
garg2022autosomalrecessiveprogeroid pages 5-6
https://doi.org/10.1016/j.xhgg.2022.100148
https://doi.org/10.1016/j.ebiom.2024.105476
https://doi.org/10.3390/cells10051164
https://doi.org/10.1126/sciadv.adn7191
https://doi.org/10.1042/bst20231236
https://doi.org/10.1038/s41421-020-00198-2
https://doi.org/10.1093/pnasnexus/pgae269
https://doi.org/10.1016/j.molcel.2019.01.002
https://doi.org/10.1172/jci156864
https://doi.org/10.3390/cells10051164,
https://doi.org/10.1126/sciadv.adn7191,
https://doi.org/10.1016/j.xhgg.2022.100148,
https://doi.org/10.1093/pnasnexus/pgae269,
https://doi.org/10.1038/s41421-020-00198-2,
https://doi.org/10.1042/bst20231236,
https://doi.org/10.1016/j.molcel.2019.01.002,
https://doi.org/10.1016/j.ebiom.2024.105476,
https://doi.org/10.1172/jci156864,

📄 View Raw YAML

id: Q9P0U1
gene_symbol: TOMM7
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  TOMM7 is a small single-pass mitochondrial outer membrane TOM complex subunit.
  It is not the TOM pore or a standalone transporter; instead it regulates TOM
  core assembly, stability, and oligomeric organization, and it has a supported
  mitochondrial quality-control role in PINK1 stabilization/activation and
  PINK1-Parkin mitophagy signaling after mitochondrial depolarization.
existing_annotations:
- term:
    id: GO:0005742
    label: mitochondrial outer membrane translocase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      Correct phylogenetic inference. TOMM7 is a conserved small TOM subunit in
      the mitochondrial outer membrane translocase complex.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/TOMM7/TOMM7-deep-research-falcon.md
      supporting_text: "TOMM7 is an **outer mitochondrial membrane** subunit of the TOM machinery."
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      Correct UniProt-derived localization. TOMM7 is a single-pass outer
      mitochondrial membrane TOM subunit.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
- term:
    id: GO:0005742
    label: mitochondrial outer membrane translocase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      Correct InterPro-derived annotation. TOMM7 is a Tom7-family small TOM
      complex subunit.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
- term:
    id: GO:0030150
    label: protein import into mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      Correct as a broad TOM pathway consequence but not TOMM7's most specific
      role. TOMM7 regulates TOM complex assembly/stability and supports import
      indirectly through the TOM complex.
    action: KEEP_AS_NON_CORE
    reason: Matrix import is one route through TOM; TOMM7's core role is TOM complex regulation.
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12198123
  review:
    summary: >-
      Protein binding is too generic. The relevant result is TOMM7 insertion and
      assembly into the TOM complex, captured by TOM complex and assembly terms.
    action: REMOVE
    reason: Protein binding is uninformative for TOMM7 function.
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30021884
  review:
    summary: >-
      Histone crosslinking protein binding is not part of the curated TOMM7
      mitochondrial outer membrane/TOM function.
    action: REMOVE
    reason: Protein binding is uninformative and likely unrelated to TOMM7 core function.
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  review:
    summary: >-
      Generic OpenCell protein binding does not capture TOMM7's function as a
      regulatory/structural TOM complex subunit.
    action: REMOVE
    reason: Protein binding is uninformative; complex and process annotations are more appropriate.
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
- term:
    id: GO:0030150
    label: protein import into mitochondrial matrix
  evidence_type: TAS
  original_reference_id: PMID:15644312
  review:
    summary: >-
      Broad but valid for the TOM import pathway. TOMM7 contributes indirectly
      through TOM complex organization rather than acting as the matrix-import
      motor or pore.
    action: KEEP_AS_NON_CORE
    reason: Matrix import is a TOM pathway outcome but not TOMM7's most specific function.
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: NAS
  original_reference_id: PMID:18331822
  review:
    summary: >-
      Correct localization. TOMM7 is a small outer mitochondrial membrane subunit
      of the TOM machinery.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-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 TOM biology is related, but TOMM7 is not an independent insertase.
      The specific supported role is TOM complex assembly/stability and
      oligomeric-state regulation.
    action: MODIFY
    reason: Replace outer membrane insertion with TOM complex assembly/stability.
    proposed_replacement_terms:
    - id: GO:0070096
      label: mitochondrial outer membrane translocase complex assembly
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
- term:
    id: GO:0140596
    label: TOM complex
  evidence_type: NAS
  original_reference_id: PMID:18331822
  review:
    summary: >-
      Correct and specific. TOMM7 is a TOM core/holo complex subunit adjacent to
      TOM40/TOM22 and the other small Tom proteins.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  review:
    summary: >-
      Correct but too general. TOMM7 is specifically a mitochondrial outer
      membrane TOM complex subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
- term:
    id: GO:0005742
    label: mitochondrial outer membrane translocase complex
  evidence_type: TAS
  original_reference_id: PMID:24270810
  review:
    summary: >-
      Accepted. The TOMM7/PINK1-Parkin evidence is consistent with TOMM7 acting
      at the TOM complex.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
- term:
    id: GO:0031647
    label: regulation of protein stability
  evidence_type: IMP
  original_reference_id: PMID:24270810
  review:
    summary: >-
      Accepted for the PINK1 context. TOMM7 is required for efficient PINK1
      stabilization/activation at the TOM complex after mitochondrial
      depolarization.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
- term:
    id: GO:1903749
    label: positive regulation of protein localization to mitochondrion
  evidence_type: IMP
  original_reference_id: PMID:24270810
  review:
    summary: >-
      Accepted as a PINK1-related annotation. TOMM7 supports PINK1 accumulation
      at damaged mitochondria/TOM after depolarization.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
- term:
    id: GO:1905091
    label: positive regulation of type 2 mitophagy
  evidence_type: IMP
  original_reference_id: PMID:24270810
  review:
    summary: >-
      Accepted. TOMM7 enables PINK1 stabilization/activation at TOM and
      downstream Parkin recruitment, supporting PINK1-Parkin mitophagy signaling.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5205661
  review:
    summary: >-
      Accepted. Reactome places TOMM7 at the mitochondrial outer membrane in
      TOM/PINK1 pathway context.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:12198123
  review:
    summary: >-
      Correct but too general. TOMM7 is specifically an outer membrane TOM
      complex subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by mitochondrial outer membrane and TOM complex annotations.
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
- term:
    id: GO:0005742
    label: mitochondrial outer membrane translocase complex
  evidence_type: IDA
  original_reference_id: PMID:12198123
  review:
    summary: >-
      Accepted. PMID:12198123 directly addresses insertion and assembly of human
      TOM7 into the TOM complex.
    action: ACCEPT
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
- term:
    id: GO:0008320
    label: protein transmembrane transporter activity
  evidence_type: TAS
  original_reference_id: PMID:15644312
  review:
    summary: >-
      TOMM7 is not the TOM protein-conducting pore. Its role is regulatory and
      structural within the TOM complex rather than direct transporter activity.
    action: REMOVE
    reason: >-
      TOMM7 regulates TOM complex assembly/stability but does not independently
      enable protein transmembrane transporter activity.
    additional_reference_ids:
    - file:human/TOMM7/TOMM7-deep-research-falcon.md
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- 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: []
- id: PMID:12198123
  title: Insertion and assembly of human tom7 into the preprotein translocase complex
    of the outer mitochondrial membrane.
  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:24270810
  title: High-content genome-wide RNAi screens identify regulators of parkin upstream
    of mitophagy.
  findings: []
- id: PMID:30021884
  title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry
    in Intact Cell Nuclei.
  findings: []
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: Reactome:R-HSA-5205661
  title: Pink1 is recruited from the cytoplasm to the mitochondria
  findings: []
- id: file:human/TOMM7/TOMM7-deep-research-falcon.md
  title: Falcon deep research report for human TOMM7
  findings: []
core_functions:
- description: >-
    TOMM7 is a regulatory/structural small TOM subunit that modulates TOM complex
    assembly, stability, and oligomeric organization at the mitochondrial outer
    membrane.
  supported_by:
  - reference_id: file:human/TOMM7/TOMM7-deep-research-falcon.md
    supporting_text: "Functionally, TOMM7 is best classified as a **non-enzymatic regulatory/structural subunit**"
  - reference_id: file:human/TOMM7/TOMM7-deep-research-falcon.md
    supporting_text: "TOMM7 is an **outer mitochondrial membrane** subunit of the TOM machinery."
  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
- description: >-
    TOMM7 links the TOM complex to mitochondrial quality control by enabling
    PINK1 stabilization/activation at TOM and downstream PINK1-Parkin mitophagy
    signaling after mitochondrial damage.
  supported_by:
  - reference_id: file:human/TOMM7/TOMM7-deep-research-falcon.md
    supporting_text: "TOMM7 is also **required for efficient PINK1 stabilization/activation at the TOM complex**"
  directly_involved_in:
  - id: GO:1905091
    label: positive regulation of type 2 mitophagy
  - id: GO:0031647
    label: regulation of protein stability
  - id: GO:1903749
    label: positive regulation of 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 TOMM7 structural features separately control TOM oligomeric stability
    and PINK1 arrest/activation at the TOM complex?
  experts: []
- question: >-
    Why do different TOMM7 disease alleles produce selective developmental,
    metabolic, or cerebrovascular phenotypes despite retention of mitochondrial
    localization?
  experts: []
suggested_experiments:
- hypothesis: >-
    TOMM7 disease variants selectively weaken TOMM7-TOMM40/TOMM22 interactions,
    altering TOM assembly and PINK1 signaling without uniformly abolishing import.
  description: >-
    Compare endogenous TOMM7 knockout/rescue with p.W25R and p.P29L alleles for
    TOM complex assembly, TOMM40/TOMM22 interaction, import of representative
    mitochondrial precursors, PINK1 stabilization, Parkin recruitment, and
    endothelial/iPSC metabolic phenotypes.
  experiment_type: endogenous rescue, TOM assembly assay, and mitophagy assay

Gene Description

Existing Annotations Review

Core Functions

TOMM7 is a regulatory/structural small TOM subunit that modulates TOM complex assembly, stability, and oligomeric organization at the mitochondrial outer membrane.

TOMM7 links the TOM complex to mitochondrial quality control by enabling PINK1 stabilization/activation at TOM and downstream PINK1-Parkin mitophagy signaling after mitochondrial damage.