tomm-22 encodes the C. elegans ortholog of TOM22 (TOMM-22), a small single-pass integral protein of the mitochondrial outer membrane and a central receptor/scaffold subunit of the TOM complex (translocase of the outer mitochondrial membrane). The TOM complex is the main entry gate through which nucleus-encoded, cytosolically synthesized preproteins are imported into mitochondria. TOMM-22 exposes an N-terminal cytosolic domain that, together with the peripheral receptor TOMM-20, recognizes the N-terminal targeting presequences of incoming preproteins and helps transfer them toward the TOMM-40 import channel; its transmembrane segment and intermembrane-space tail help organize the dimeric TOM core and hand substrates to the inner-membrane TIM23 machinery. In C. elegans, reducing TOMM-22 lowers mitochondrial protein-import capacity; the resulting import stress activates the ATFS-1-dependent mitochondrial unfolded protein response (marked by hsp-6 induction) and impairs the food-coupled secretion of the insulin-like peptide DAF-28, while secretion of other neuropeptides is unaffected. Because mitochondrial import stress modulates the UPRmt and organismal aging, partial loss of tomm-22 is used experimentally to trigger import-associated UPRmt.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005742 mitochondrial outer membrane translocase complex | IBA GO_REF:0000033 | ACCEPT | Summary: Core cellular-component annotation. TOMM-22 is a conserved receptor/scaffold subunit of the TOM complex (mitochondrial outer membrane translocase complex). Complex membership is supported by the Tom22 family assignment (IPR005683/PF04281), the UniProt SUBUNIT statement, and worm studies that treat tomm-22 as a TOM-complex component. Supporting Evidence: PMID:24662282 These included tomm-22, a component of the TOM complex which functions as a translocase in the outer mitochondrial membrane PMID:35608535 Genes encoding TOM complex proteins, including tomm-20, tomm-22, and tomm-40, were enhanced one- to twofold |
| GO:0030150 protein import into mitochondrial matrix | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological-process annotation. As a TOM receptor/scaffold subunit, TOMM-22 functions in the import of nucleus-encoded, presequence-bearing preproteins destined for the matrix. Worm evidence shows tomm-22 is required for mitochondrial protein import capacity: its knockdown abolishes the import improvement seen on UPRmt activation. Supporting Evidence: PMID:35608535 knocking down TOM complex component tomm-22 abolished the effect of cco-1 RNAi on improving import capacity PMID:21264209 it acts along with other components, such as Tom20 and Tom22, to import proteins into the mitochondria |
| GO:0008320 transmembrane protein transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Accept as a contribution (contributes_to) to the TOM complex's protein transmembrane transport activity. TOMM-22 is the presequence receptor/scaffold that recognizes targeting signals and hands preproteins to the TOMM-40 pore; it does not itself form the conducting channel, so the contributes_to qualifier is appropriate rather than asserting standalone transporter activity. Reason: TOMM-40 is the beta-barrel conducting pore of the TOM complex; TOMM-22 provides the receptor/scaffold function needed for import. Retain only as a complex-level contribution. Supporting Evidence: PMID:35733257 Tom20 and Tom22 are involved in targeting signal recognition during protein import PMID:40522955 the primary role of tomm-22 is a mitochondrial outer membrane transporter rather than a mitochondrial UPR stress regulator |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Correct core subcellular location. TOMM-22 is a single-pass integral protein of the mitochondrial outer membrane (cytosolic N-terminus, single transmembrane helix, intermembrane-space C-terminus). Supporting Evidence: PMID:40522955 TOMM-22 is involved in protein transport across the outer mitochondrial membrane UniProt:O17287 Mitochondrion outer membrane |
| GO:0006886 intracellular protein transport | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: True but over-general. This is an InterPro2GO inference from the Tom22 domain (IPR005683) and is a broad parent of the specific process the protein performs, protein import into mitochondria (GO:0030150), which is separately annotated and represents the core biological process. Kept as a correct but non-core annotation. Reason: Generic ancestor of the more informative GO:0030150 (protein import into mitochondrial matrix); does not add specificity beyond it. |
| GO:0005741 mitochondrial outer membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Same mitochondrial-outer-membrane location as the IEA annotation, here transferred by sequence similarity from human TOMM22 (Q9NS69). Consistent with the conserved single-pass outer-membrane topology of the Tom22 family. Supporting Evidence: UniProt:O17287 Mitochondrion outer membrane |
| GO:0140436 mitochondrial signal sequence receptor activity | ISS PMID:35733257 Structural basis of Tom20 and Tom22 cytosolic domains as the... | NEW | Summary: Proposed molecular-function annotation capturing TOMM-22's core, evolutionarily conserved activity as a mitochondrial targeting-sequence (presequence) receptor that, together with TOMM-20, recognizes incoming preproteins. This activity is not currently represented in the worm GOA (which carries only the complex-level contributes_to transporter term); it is proposed here on the basis of the conserved Tom22 presequence-receptor function and the UniProt transit-peptide-receptor annotation. GO:0030943 (mitochondrion targeting sequence binding), originally proposed here, is now obsolete; the row uses its designated receptor replacement GO:0140436 (mitochondrial signal sequence receptor activity). Supporting Evidence: PMID:35733257 Tom20 and Tom22 are involved in targeting signal recognition during protein import PMID:21264209 TOM20 and TOM22, are receptors that recognize different subgroups of mitochondria-destined preproteins |
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Download this section (compressed HTML)Q: Does C. elegans TOMM-22 bind mitochondrial targeting presequences directly at cis and trans sites, as demonstrated for yeast and human Tom22, and does it have the chaperone-like activity reported for mammalian Tom22?
Q: Is tomm-22 essential in C. elegans, and how does a genetic null differ from RNAi knockdown in developmental and mitochondrial-import phenotypes?
Q: Which classes of C. elegans mitochondrial preproteins depend most on TOMM-22 versus the peripheral receptor TOMM-20?
Experiment: Purify recombinant TOMM-22 cytosolic and IMS domains and measure binding to synthetic mitochondrial presequence peptides (e.g. by ITC/fluorescence anisotropy); test aggregation-suppression (chaperone-like) activity on a model preprotein substrate.
Hypothesis: C. elegans TOMM-22 is a bona fide presequence receptor with cis (cytosolic) and trans (IMS) binding sites.
Type: biochemical binding / chaperone assay
Experiment: Generate a tomm-22 null allele and quantify import of matrix-targeted reporters (e.g. an MTS::GFP) versus wild type and tomm-40 mutants, alongside viability and UPRmt (hsp-6p::gfp) readouts.
Hypothesis: TOMM-22 is required for bulk mitochondrial protein import in C. elegans but less essential than the TOMM-40 channel.
Type: genetics / in vivo import assay
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The biochemical activity of C. elegans TOMM-22 itself has never been directly measured. Its presequence-binding (cis/trans receptor) function, its chaperone-like activity, and its preprotein substrate-class specificity are all inferred from yeast and human orthologs; every direct worm experiment assays loss-of-function phenotypes (UPRmt induction, DAF-28 secretion, import-capacity requirement) rather than the activity of the TOMM-22 protein.
OPEN BIOLOGYCURATION MF_DARK
What is known: It is firmly established that TOMM-22 is a Tom22-family single-pass outer-membrane subunit of the TOM complex, that reducing it activates the hsp-6/UPRmt response and impairs DAF-28/insulin secretion (Billing 2011), and that tomm-22 is required for mitochondrial import capacity in worm (Xin 2022). The conserved structural role (presequence receptor with cis and trans sites, chaperone-like activity, TOM-core scaffold) is well characterized in yeast and human Tom22.
Significance: tomm-22 is routinely used as a generic "import-defective" RNAi background in worm UPRmt and aging studies, yet whether the worm protein reproduces the cis/trans presequence receptor and chaperone-like activities of its mammalian ortholog, or has organism-specific substrate preferences, is untested. Anchoring the molecular function in worm data would strengthen the interpretation of that large phenotypic literature.
What would resolve it: In vitro presequence/preprotein-binding and aggregation-suppression assays with recombinant C. elegans TOMM-22 cytosolic and IMS domains; structure-function analysis of a tagged worm TOMM-22; substrate-class profiling of import defects on tomm-22 loss.
Provenance (the field's own admissions):
Gap: Whether tomm-22 is essential in C. elegans is unresolved. Only partial-knockdown (RNAi) data exist, and no null/deletion allele has been characterized, so it is unknown whether complete loss of TOMM-22 is lethal (as for TOM22 in mouse) or tolerated.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: tomm-22(RNAi) reproducibly activates UPRmt and impairs DAF-28 secretion but is much milder than tomm-40(RNAi): it does not cause the highly penetrant larval arrest seen on tomm-40 depletion. This is a knockdown, not a genetic null.
Significance: The severity gradient among TOM subunits (tomm-40 >> tomm-22/tomm-20) is used to argue that TOMM-22 is not as rate-limiting as the TOM40 channel; a defined null is needed to test essentiality and separate residual RNAi activity from a genuine partial requirement.
What would resolve it: Characterize a tomm-22 deletion/null allele (e.g. CRISPR or an existing balanced deletion) for viability, developmental arrest, and mitochondrial import phenotypes.
Provenance (the field's own admissions):
Gap: The existence, expression, and function of the shorter tomm-22 isoform b (O17287-2), which lacks residues 1-94 and therefore essentially the entire cytosolic receptor domain and transmembrane anchor, are uncharacterized.
OPEN BIOLOGYCURATION RESIDUAL_SUBGAP
What is known: UniProt annotates two alternative-splicing products of tomm-22; isoform b differs from the full-length isoform a by a large N-terminal deletion. No transcript-level, protein- level, or functional data distinguish the isoforms.
Significance: An isoform lacking the receptor domain and membrane anchor could be non-functional, regulatory, or an annotation artifact; resolving this affects how TOMM-22 dosage and domain requirements are interpreted.
What would resolve it: Isoform-specific RT-PCR / long-read transcriptomics to confirm isoform b, and isoform-specific rescue/localization to test whether it retains any activity.
Provenance (the field's own admissions):
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