Affinage

TOMM7

Mitochondrial import receptor subunit TOM7 homolog · UniProt Q9P0U1

Length
55 aa
Mass
6.2 kDa
Annotated
2026-04-28
17 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TOMM7 encodes a small tail-anchored subunit of the mitochondrial outer membrane TOM translocase complex that functions as a modulator of complex assembly and a gatekeeper for selective protein import. Its transmembrane segment directly contacts the central pore component Tom40, and Tom7 destabilizes TOM complex assembly at two stages: by antagonizing Tom5/Tom6 during early Tom40 integration at the SAM complex, and by sequestering Mdm10 away from the SAM-Mdm10 complex to delay late Tom22–Tom40 association (PMID:8641278, PMID:21059357, PMID:21036907). Tom7 is specifically required for PINK1 import arrest on depolarized mitochondria, opposing OMA1-mediated PINK1 cleavage in a regulated tug of war that determines whether PINK1/Parkin-dependent mitophagy is activated (PMID:30733118, PMID:41276015). Biallelic loss-of-function variants in human TOMM7 cause a progeroid/syndromic short stature disorder characterized by altered mitochondrial protein import, mitochondrial uncoupling, and developmental delay (PMID:36282599, PMID:36299998).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1996 High

    Identification of Tom7 as a small TOM complex subunit with a destabilizing role in receptor–pore interactions established that TOM assembly is actively modulated rather than merely driven by affinity, and that Tom7 opposes Tom6 function.

    Evidence Yeast gene deletion with in vitro import assays, native complex analysis, and synthetic lethality (tom7Δ tom20Δ, tom7Δ tom6Δ)

    PMID:8641278

    Open questions at the time
    • Direct physical contacts between Tom7 and other TOM subunits not yet mapped
    • Mechanism of how Tom7 destabilizes receptor–pore interaction unknown
  2. 2001 High

    Cross-linking experiments resolved that Tom7 makes direct physical contact with Tom40 through its transmembrane domain, establishing that Tom7 acts on the pore itself rather than indirectly through receptors.

    Evidence Chemical cross-linking and in vitro assembly/competition assays in Neurospora crassa mitochondria

    PMID:11278536

    Open questions at the time
    • Residue-level contacts not defined
    • Whether human Tom7 contacts Tom40 identically was unconfirmed
  3. 2002 High

    Characterization of human Tom7 as a tail-anchored protein that assembles stepwise into TOM complexes via a ~120 kDa Tom40-containing intermediate before joining the ~380 kDa holo-complex established the assembly pathway in mammalian cells and identified Tom22 as rate-limiting for the final step.

    Evidence In vitro import into HeLa mitochondria, blue native PAGE, antibody supershift, Tom22 overexpression

    PMID:11943179 PMID:12198123

    Open questions at the time
    • Functional consequences of Tom7 loss in human cells not yet tested
    • Role of the conserved transmembrane proline in assembly kinetics not fully resolved
  4. 2006 High

    Discovery that Tom7 promotes segregation of Mdm10 away from the SAM(holo) complex explained its paradoxical dual role — promoting porin assembly while antagonizing Tom40 assembly — by placing Tom7 as a regulator of SAM complex composition.

    Evidence Yeast genetic deletion, co-immunoprecipitation, native gel electrophoresis, in vitro import/assembly

    PMID:16760475

    Open questions at the time
    • Direct Tom7–Mdm10 interaction not yet proven by cross-linking
    • Whether Mdm10 regulation is conserved in mammals unknown
  5. 2010 High

    In vivo site-specific photocross-linking confirmed that Tom7 contacts both Tom40 (via its transmembrane segment) and Mdm10, and functional assays showed Tom7 acts inhibitorily at two distinct steps: early Tom40 assembly at SAM (opposing Tom5/Tom6) and late Tom22 integration (via Mdm10 sequestration).

    Evidence Site-specific photocross-linking in yeast, genetic deletion, in vitro assembly kinetics

    PMID:21036907 PMID:21059357

    Open questions at the time
    • Structural basis for Tom7's opposing effects at each step unresolved
    • Mammalian equivalents of the two-step inhibition not demonstrated
  6. 2018 Medium

    Tom7 was shown to regulate selective mitochondrial import of Rac1 in endothelial cells, linking TOM complex modulation to redox signaling and cerebrovascular angiogenesis — the first demonstration of a tissue-specific physiological role for Tom7.

    Evidence Zebrafish genetic screen, Tomm7 knockout mice, endothelial-specific rescue, mitochondrial import assays

    PMID:30354240

    Open questions at the time
    • Whether Rac1 import regulation is direct or indirect through altered TOM complex composition unclear
    • Mechanism connecting Rac1 mitochondrial import to redox signaling incompletely defined
  7. 2019 High

    Tom7 was identified as specifically required for PINK1 import arrest on depolarized mitochondria, with OMA1 acting as the opposing force; this 'tug of war' model explained how the TOM complex acts as a decision point for PINK1 stabilization and mitophagy initiation.

    Evidence Tom7 deletion and OMA1 suppression in mammalian cells, PINK1 transmembrane-domain mutagenesis, cleavage and localization assays

    PMID:30733118

    Open questions at the time
    • Structural basis for how Tom7 retains PINK1 at the outer membrane unknown
    • Whether Tom7 directly contacts PINK1 or acts indirectly through Tom40 conformation not resolved
  8. 2022 Medium

    Identification of biallelic TOMM7 variants (p.Pro29Leu and p.Trp25Arg) as causes of progeroid/syndromic short stature in humans demonstrated that Tom7 is essential for normal development and that its loss causes mitochondrial uncoupling with altered import of oxidative phosphorylation components.

    Evidence Exome sequencing in affected families, quantitative mitochondrial proteomics, respiration assays in patient fibroblasts and Tomm7 mutant mice

    PMID:36282599 PMID:36299998

    Open questions at the time
    • Only two families reported; genotype-phenotype spectrum remains narrow
    • Whether mitochondrial uncoupling is a direct consequence of altered import or secondary unclear
    • Structural impact of missense variants on Tom7–Tom40 interaction not determined
  9. 2025 Medium

    TOMM7 was shown to regulate PINK1/Parkin-mediated mitophagy in kidney tubular cells by controlling PLA2G6 redistribution between nucleus and mitochondria, with ZBTB12 identified as a transcriptional repressor of TOMM7, extending Tom7's role to organ-specific damage responses.

    Evidence Tomm7 overexpression in db/db mice, PLA2G6 localization assays, ZBTB12 transcription factor identification

    PMID:41276015

    Open questions at the time
    • Whether PLA2G6 is a direct import substrate of the Tom7-modified TOM complex not established
    • ZBTB12 regulation of TOMM7 confirmed in single system only
    • Relevance of this pathway to non-renal tissues unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for how Tom7 retains PINK1 at the TOM channel, whether Tom7 directly modulates the Tom40 pore conformation versus acting as a steric block, and how tissue-specific import selectivity (Rac1, PLA2G6) is determined by a ubiquitously expressed small subunit.
  • No high-resolution structure of Tom7 within the mammalian TOM complex
  • No reconstituted system demonstrating substrate-selective gating by Tom7
  • Transcriptional regulation of TOMM7 across tissues poorly characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0005198 structural molecule activity 4
Localization
GO:0005739 mitochondrion 6
Pathway
R-HSA-9609507 Protein localization 6 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-9612973 Autophagy 2
Partners
MDM10OMA1PINK1TOMM22TOMM40TOMM5TOMM6
Complex memberships
TOM complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Tom7 is a small integral membrane subunit of the mitochondrial outer membrane translocase (TOM complex) that destabilizes the interaction between receptors Tom20 and Tom22 and the import pore component Tom40, while Tom6 stabilizes this interaction; deletion of Tom7 inhibits import of outer membrane protein porin and delays two-step import of matrix-destined preproteins, and genetic synthetic lethality of tom7Δ tom20Δ and tom7Δ tom6Δ double mutants confirms functional relationships. Genetic deletion, in vitro import assays, native protein complex analysis, double-mutant synthetic growth defect analysis The EMBO journal High 8641278
2001 Tom7 in Neurospora crassa is in direct physical contact with the major pore component Tom40, as shown by cross-linking, and its precursor can insert into the outer membrane in vitro and assemble into authentic TOM complexes via a pathway that shares a binding site with the general import pathway and depends on receptor components. Cross-linking, in vitro import and assembly assays, competition assays The Journal of biological chemistry High 11278536
2002 Human Tom7 is a tail-anchored protein imported into mitochondria in a nucleotide-independent manner, anchored to the outer membrane with its C terminus facing the intermembrane space; it assembles first into an ~120 kDa intermediate containing Tom40 but lacking receptors, then into the ~380 kDa TOM complex additionally containing Tom22; Tom22 is rate-limiting for this final assembly step. In vitro import into HeLa mitochondria, blue native electrophoresis, supershift antibody analysis, Tom22 overexpression The Journal of biological chemistry High 12198123
2002 Tom7 is a tail-anchored protein whose carboxy-terminal 33 amino acids contain mitochondrial outer membrane targeting information, and a conserved proline residue within the transmembrane segment is required for efficient targeting to the outer membrane. Deletion/truncation mutagenesis, proline point mutation, subcellular targeting assays FEBS letters Medium 11943179
2006 Tom7 promotes segregation of the SAM complex subunit Mdm10 into a low-molecular-mass form away from the SAM(holo) complex; deletion of Tom7 increases the fraction of Mdm10 in the SAM(holo) complex, explaining the opposing roles of Tom7 (promotes porin assembly, antagonizes Tom40 assembly) versus Mdm10 (promotes Tom40 assembly). Genetic deletion, co-immunoprecipitation, native gel electrophoresis, in vitro import/assembly assays The Journal of biological chemistry High 16760475
2010 Tom7 directly interacts with Tom40 through its transmembrane segment and with Mdm10, as shown by site-specific photocross-linking in vivo; Tom7 recruits Mdm10 to enhance its association with the MMM1 complex and regulates the timing of Tom40 release from the TOB/SAM complex for subsequent assembly into the TOM40 complex. Site-specific photocross-linking in vivo, in vitro import assays, Tom7 overexpression/depletion The Journal of biological chemistry High 21036907
2010 Tom7 plays inhibitory roles at two distinct steps in TOM complex biogenesis: (1) antagonizing Tom5 and Tom6 at an early stage of Tom40 assembly at the SAM complex, and (2) interacting with Mdm10 not bound to the SAM complex to promote dissociation of the SAM-Mdm10 complex, thereby delaying assembly of Tom22 with Tom40 at a late stage. Genetic deletion, native gel electrophoresis, in vitro import assays, complex assembly tracking Journal of molecular biology High 21059357
2019 Tom7 is required for PINK1 import arrest at the outer mitochondrial membrane upon mitochondrial depolarization; deletion of Tom7 causes PINK1 to be imported into depolarized mitochondria and cleaved by the OMA1 protease rather than accumulating at the outer membrane. A negatively charged amino acid cluster motif just C-terminal to the PINK1 transmembrane domain mediates this retention, and Tom7 and OMA1 act in a 'tug of war' to determine PINK1 fate. Tom7 deletion, OMA1 suppression, mutagenesis of PINK1 motif, PINK1 localization and cleavage assays Molecular cell High 30733118
2018 Tomm7 in endothelial cells controls cerebrovascular network formation by regulating the mitochondrial import of Rac1; Tomm7 deficiency causes increased import of Rac1 into mitochondria, activating mitochondrial Rac1-coupled redox signaling that impairs angiogenesis and underlies cerebrovascular malformation. Zebrafish loss-of-function genetic screen, Tomm7 knockout mice, endothelial-specific transgenic rescue, mitochondrial import assays, vascular imaging Arteriosclerosis, thrombosis, and vascular biology Medium 30354240
2022 A homozygous missense variant (p.Pro29Leu) in human TOMM7 causes a progeroid syndrome with severe growth retardation; proband-derived fibroblasts show altered mitochondrial protein import with increased abundance of oxidative phosphorylation proteins and reduced phospholipid metabolism proteins, and elevated basal and maximal oxygen consumption rates. Exome sequencing, quantitative mitochondrial proteomics, oxygen consumption rate measurement in patient fibroblasts The Journal of clinical investigation Medium 36282599
2022 A homozygous hypomorphic variant in TOMM7 (p.Trp25Arg) causes syndromic short stature and developmental delay; Tomm7 mutant mice show mitochondrial uncoupling with increased oxygen consumption but normal ETC function, suggesting Tomm7 deficiency uncouples oxidation from ATP synthesis without impairing TCA cycle or ETC. Mouse knockout and knock-in models, oxygen consumption assays with ETC inhibitors, phenotypic characterization HGG advances Medium 36299998
2025 TOMM7 regulates PINK1/Parkin-mediated mitophagy in kidney tubular cells by modulating the intracellular redistribution of phospholipase PLA2G6 between the nucleus and mitochondria; TOMM7 overexpression in db/db mice restores PINK1/Parkin-mediated mitophagy and alleviates tubular injury. ZBTB12 was identified as a transcriptional repressor of TOMM7. Tomm7 overexpression in db/db mice, PLA2G6 localization assays, ZBTB12 transcription factor identification, tubular cell in vitro models Kidney international Medium 41276015
2025 CRISPR knockout of TOM7 in human iPSC-derived dopaminergic neurons decreases ubiquitin pSer65 upregulation during mitophagy activation, confirming Tom7's role in the PINK1-PARKIN mitophagy pathway in a human neuronal model. High-throughput arrayed CRISPR-Cas9 screen, high-content immunofluorescence imaging, machine learning analysis in iPSC-derived dopaminergic neurons bioRxivpreprint Medium bio_10.1101_2025.06.10.658840

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1. Molecular cell 138 30733118
1996 Tom7 modulates the dynamics of the mitochondrial outer membrane translocase and plays a pathway-related role in protein import. The EMBO journal 137 8641278
2002 Insertion and assembly of human tom7 into the preprotein translocase complex of the outer mitochondrial membrane. The Journal of biological chemistry 114 12198123
2010 Tom7 regulates Mdm10-mediated assembly of the mitochondrial import channel protein Tom40. The Journal of biological chemistry 87 21036907
2006 Mitochondrial protein sorting: differentiation of beta-barrel assembly by Tom7-mediated segregation of Mdm10. The Journal of biological chemistry 86 16760475
2010 Biogenesis of mitochondria: dual role of Tom7 in modulating assembly of the preprotein translocase of the outer membrane. Journal of molecular biology 74 21059357
2001 Assembly of Tom6 and Tom7 into the TOM core complex of Neurospora crassa. The Journal of biological chemistry 55 11278536
2002 A conserved proline residue is present in the transmembrane-spanning domain of Tom7 and other tail-anchored protein subunits of the TOM translocase. FEBS letters 42 11943179
2022 Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant. The Journal of clinical investigation 23 36282599
2018 Endothelial Mitochondrial Preprotein Translocase Tomm7-Rac1 Signaling Axis Dominates Cerebrovascular Network Homeostasis. Arteriosclerosis, thrombosis, and vascular biology 18 30354240
2022 A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay. HGG advances 13 36299998
2018 TOM7 silencing exacerbates focal cerebral ischemia injury in rat by targeting PINK1/Beclin1-mediated autophagy. Behavioural brain research 12 30468788
2015 [Association of genetic variants in TOMM7 gene and gene environment interaction with type 2 diabetes in Chinese Dong population]. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 3 25652373
2025 Mitochondrial protein TOMM7 alleviates diabetic kidney disease by regulating mitophagy via intracellular redistribution of phospholipase PLA2G6. Kidney international 1 41276015
2026 Single-cell and Bulk RNA-Seq Analyses Reveal TOMM7-mediated Multi-cell Death Mechanisms Driving Muscle-invasive Bladder Cancer Progression. Recent patents on anti-cancer drug discovery 0 41540546
2025 Growth Hormone Response in a Child With a Homozygous TOMM7 Mutation: Novel Therapeutic Insights. The American journal of case reports 0 41460760
2005 Cloning and characterization of TOM7-like gene in wheat. Yi chuan xue bao = Acta genetica Sinica 0 15759864