Gene: MTCH2 (mitochondrial carrier homolog 2; synonyms MIMP, HSPC032). Human.
UniProt Q9Y6C9, 303 aa. Paralogue: MTCH1 (Q9NZJ7) — reviewed separately in
genes/human/MTCH1/MTCH1-ai-review.yaml; the two reviews are written to agree.
This file was created as part of an update that folded four papers postdating the
previous version of the review into it: PMID:42308315 (Sci Adv 2026, structure),
PMID:42056306 (Nat Struct Mol Biol 2026, BAX/BAK), PMID:41044057 (Nat Commun 2025,
CPT1) and PMID:40704594 (J Cell Sci 2025, yeast MIM complementation).
Established by Guna et al. 2022 with genome-wide CRISPRi, in vitro insertion into
mitochondria from knockout cells, and reconstitution of purified protein into
proteoliposomes
PMID:36264797. Substrate range is alpha-helical and broad
PMID:36264797; beta-barrels are not MTCH2 substrates.
This settles the long-running topology disagreement (five TMs, not six) and gives the
activity a physical basis — a groove that lowers the barrier to moving a soluble domain
across the bilayer — rather than leaving "insertase" as a phenotypic label.
GOA carries no transporter molecular-function term for MTCH2. The only MF terms in
MTCH2-goa.tsv are GO:0032977 (membrane insertase activity, IDA) and GO:0005515 (protein
binding, IPI x3). That absence is the correct and defensible position.
However, the name "Mitochondrial carrier homolog 2" and the UniProt record push the other
way: KW Transport and DR TCDB; 2.A.29.25.2; the mitochondrial carrier (mc) family
[file:human/MTCH2/MTCH2-uniprot.txt "Belongs to the mitochondrial carrier (TC 2.A.29)
family."]. UniProt's GO cross-references also include an Ensembl-derived
GO:0042775 (mitochondrial ATP synthesis coupled electron transport) that does not appear
in the QuickGO GOA file.
The structural work argues the transport machinery is gone, not merely unused
PMID:42308315 and, importantly, restoring them does not help insertion
PMID:42308315.
No transport assay on purified MTCH2 has ever been published, positive or negative, so
"transport lost" is an inference from structure. Recorded as a knowledge_gap and a
suggested_experiment rather than asserted. This matches how the MTCH1 review handles the
same question.
The previous version of this review assumed the apoptotic role was secondary to insertion
("Apoptotic role may be secondary to its insertase activity"; "Likely downstream of
insertase function"). That assumption is refuted.
Three separate controls make that stick:
The authors are appropriately hedged about how absolute this is
PMID:42056306.
It is also distinct from the older tBID-recruitment role
PMID:42056306, and it has downstream
consequences beyond cell death
PMID:42056306.
Curation consequence. GO:0043065 stays KEEP_AS_NON_CORE, but for a different reason
than before: not because it is a knock-on effect, but because it is a regulatory biological
process whose molecular function is undefined. There is nothing to put in
core_functions.molecular_function for it. Recorded as a knowledge_gap (MF_DARK).
This upgrades GO:0055088 (lipid homeostasis) from an unexplained ortholog-transferred
phenotype to a role with a named partner. It is still kept non-core: whether the CPT1
effect survives an insertase-dead MTCH2 has not been tested, so it cannot yet be called a
separate activity. Note the thematic convergence with the LPA/MFN2 fusion axis and the
LPA rescue of BAX/BAK assembly — three phenotypes all pointing at MTCH2 and mitochondrial
lipid handling.
This is awkward for a framing in which MTCH2 is the insertase, but it does not contradict
MTCH2 insertase activity. The authors attribute the failure to toxicity and mislocalisation
in yeast, not to inactivity:
MTCH2's insertase activity rests on reconstitution with purified protein in proteoliposomes,
which a heterologous yeast growth assay simply does not address. Conversely, MTCH1 partially
rescues MTCH2 loss in human cells
PMID:42308315. The honest reading: both paralogues are insertases, they are
partially redundant, and they are not interchangeable in every host — which is exactly how
the MTCH1 review reads it too.
| Term | Before | After | Why |
|---|---|---|---|
| GO:0005739 mitochondrion (IBA, HTP) | MARK_AS_OVER_ANNOTATED | ACCEPT | A correct parent of a correct location; node placement not in dispute. Matches MTCH1. Also clears the missing-propagation_review warning. |
| GO:0016020 membrane (IBA) | MARK_AS_OVER_ANNOTATED, no metadata | same action + propagation_review |
WITH/FROM inspected: MGI:1929260, PANTHER:PTN001324730, UniProtKB:Q9Y6C9. Granularity objection only. MTCH2's own appearance in its own WITH/FROM is expected, not circular. |
| GO:0005515 protein binding (IPI x3) | REMOVE | MARK_AS_OVER_ANNOTATED | Project guidance; these are experimental interaction records. Matches MTCH1. |
| GO:0043065 positive regulation of apoptotic process | KEEP_AS_NON_CORE ("downstream of insertase") | KEEP_AS_NON_CORE (reason rewritten) | Insertase-independence established; kept non-core only because the MF is undefined. |
| GO:0055088 lipid homeostasis | KEEP_AS_NON_CORE ("pleiotropic") | KEEP_AS_NON_CORE (reason rewritten) | Direct CPT1 interaction supplies a mechanism. |
| GO:0010635 regulation of mitochondrial fusion | KEEP_AS_NON_CORE ("MFN insertion") | KEEP_AS_NON_CORE (reason rewritten) | Published mechanism runs through MFN2 and LPA, not through inserting the fusion machinery. |
| GO:7770059 alpha helical protein insertion into OM | absent | NEW | MTCH1 already carries it; the substrate restriction is exactly what was shown for MTCH2. |
| GO:0005515 (PMID:32296183, P56378-2) | missing from review | added | Second GOA row that had been omitted. |
| GO:0005634 nucleus (HDA) | REMOVE | REMOVE (unchanged) | Sperm-nucleus fraction; mitochondrial carry-over. Left alone — the new literature does not bear on it. |
Also fixed: five supporting_text entries attributed to the Falcon deep-research file were
paraphrases beginning "Falcon synthesis supports…" and appear nowhere in that file. They
have been replaced with verbatim quotations.
Carried into suggested_questions / suggested_experiments / knowledge_gaps:
Recorded on main before this update; preserved verbatim below. Where the two
passes disagreed, the merge notes in the review YAML say which was taken and why.
Completed the review pass over all 22 existing_annotations entries; status
moved INITIALIZED → COMPLETE (validation clean, no warnings).
Key points and changes:
propagation_review blocks to the two generic IBA CC