MTCH2 is a polytopic protein of the mitochondrial outer membrane and the defining member of a holozoan family of outer-membrane protein insertases. It mediates insertion of alpha-helical transmembrane proteins - tail-anchored, signal-anchored and multipass - into the outer membrane, but not of beta-barrel proteins, which are handled by the SAM machinery; in human cells it is the functional counterpart of the evolutionarily unrelated yeast Mim1/Mim2 (MIM) complex. Cryo-electron microscopy of the 33 kDa human protein shows that MTCH2 retains the SLC25 (mitochondrial carrier) scaffold but carries only five transmembrane helices instead of six: loss of one helix opens a lipid-accessible hydrophilic groove, stabilised by a C-terminal domain unique to the MTCH family, which lowers the energetic barrier to moving a substrate's soluble domain across the bilayer. The family has also lost the interhelical salt bridges that canonical carriers use for alternating access. Despite the gene name "mitochondrial carrier homolog", no transported substrate has ever been demonstrated for MTCH2 and there is no evidence that it is a carrier. Its paralogue MTCH1 shares the fold and also has insertase activity, and MTCH1 alone can replace the yeast MIM complex, whereas MTCH2 expressed in yeast is toxic and mislocalises largely to the endoplasmic reticulum, so the two paralogues are not interchangeable in every context. MTCH2 has a second, genetically separable role in apoptosis: it concentrates next to BAX and BAK assemblies specifically under apoptotic conditions and promotes their higher-order oligomerisation and apoptotic pore growth, with consequences for mitochondrial DNA release and cGAS-STING signalling. This activity persists with an insertase-dead MTCH2 mutant, is not shared by MTCH1, and is restored by exogenous lysophosphatidic acid, indicating a lipid-dependent rather than insertion-dependent mechanism. MTCH2 additionally serves as a platform for recruitment of tBID to mitochondria, cooperates with MFN2 and lysophosphatidic acid synthesis in mitochondrial fusion, and binds carnitine palmitoyltransferase 1 directly, lowering its sensitivity to malonyl-CoA and thereby restraining mitochondrial fatty-acid influx and energy expenditure in adipocytes. Mouse loss-of-function phenotypes include altered lipid homeostasis and adipocyte biology, changed mitochondrial fusion, haematopoietic stem cell cycling and the embryonic stem cell naive-to-primed transition.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Too general β MTCH2 specifically localizes to the mitochondrial outer membrane (PMID:36264797). The IBA sources (mouse Mtch2, human MTCH1, and MTCH2 itself) are all sound OMM proteins; the issue is only that the PAINT CC assertion sits at the uninformative parent term. Reason: Not wrong (the outer membrane is part of the mitochondrion) but subsumed by the direct experimental mitochondrial outer membrane annotation (IDA, PMID:36264797); the parent-level term adds no information. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1929260 Β· mouse Mtch2 (Q791V5) SUPPORTS TRANSFER True ortholog, itself an OMM protein; supports mitochondrial localization, just at a more general level than the evidence warrants. UniProtKB:Q9NZJ7 Β· human MTCH1 SUPPORTS TRANSFER Paralog and fellow OMM insertase; consistent with mitochondrial localization. UniProtKB:Q9Y6C9 Β· human MTCH2 (self) SUPPORTS TRANSFER The target's own experimental localization evidence contributed to the IBD placement; expected, not circular. PANTHER:PTN001324730 Β· PANTHER internal tree node NOT RELEVANT Internal PAINT node identifier, not an independent evidence source. |
| GO:0016020 membrane | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Extremely generic. MTCH2 is a multi-pass protein of the mitochondrial outer membrane (PMID:36264797); "membrane" is the root CC membrane term and carries no information beyond that. Reason: Not wrong but uninformative; subsumed by the direct experimental mitochondrial outer membrane annotation (IDA, PMID:36264797). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1929260 Β· mouse Mtch2 (Q791V5) SUPPORTS TRANSFER True ortholog, an integral OMM protein; supports membrane localization at a far more specific level than this term expresses. UniProtKB:Q9Y6C9 Β· human MTCH2 (self) SUPPORTS TRANSFER The target's own experimental evidence contributed to the IBD placement; expected, not circular. PANTHER:PTN001324730 Β· PANTHER internal tree node NOT RELEVANT Internal PAINT node identifier, not an independent evidence source. Supporting Evidence: PMID:42308315 Comparison with the UCP1 structure definitively indicated that unlike a canonical SLC25, MTCH2 contained only five TMs |
| GO:0043065 positive regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic propagation of the proapoptotic role. MTCH2 is a genuine positive regulator of intrinsic apoptosis, acting both as a platform for tBID recruitment to the outer membrane and, separately, by promoting BAX and BAK higher-order self-assembly and apoptotic pore growth. Reason: Retained, but the rationale has changed with the 2026 evidence, and the earlier reading recorded here - that the apoptotic phenotype is a downstream consequence of impaired outer-membrane protein biogenesis - is no longer tenable. Flores-Romero et al. show the effect on BAX/BAK oligomerisation survives an insertase-dead MTCH2 mutant, is not reproduced by MTCH1 (which has insertase activity), and is rescued by exogenous lysophosphatidic acid, implicating lipid handling rather than protein insertion. So this is a second, separable activity of comparable biological importance to the insertase role, not a knock-on effect of it. It is nonetheless kept as non-core rather than promoted, because it is a regulatory biological process whose underlying molecular function is not yet defined - there is no molecular-function term that can presently be asserted for it (see knowledge_gaps). Supporting Evidence: PMID:42056306 we map the protein environment of the apoptotic pore using in situ proximity labeling and identify the mitochondrial carrier homolog protein MTCH2 localizing nearby BAX and BAK assemblies specifically under apoptotic conditions PMID:42056306 The effect of MTCH2 on BAX and BAK oligomerization is independent of its protein insertase activity. |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Correct. MTCH2 is a five-transmembrane-helix protein of the mitochondrial outer membrane, directly demonstrated by Guna et al. 2022 and confirmed by the 2026 cryo-EM structure. Supporting Evidence: file:human/MTCH2/MTCH2-uniprot.txt Mitochondrion outer membrane PMID:42308315 We demonstrate that MTCH2 is the defining member of a large family of mitochondrial outer membrane (OM) insertases. file:human/MTCH2/MTCH2-deep-research-falcon.md Its most directly demonstrated activitiesβprotein insertion of Ξ±-helical OMM proteins and modulation of OMM proteostasis/TA mistargetingβoccur at the OMM |
| GO:0070585 protein localization to mitochondrion | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: MTCH2 inserts proteins into the outer membrane, which is a form of protein localization to the mitochondrion, but the insertion terms are far more informative. Reason: Correct but general. GO:0045040 and the more specific GO:7770059 (alpha helical protein insertion into mitochondrial outer membrane) state what MTCH2 actually does. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary (yeast two-hybrid) interactome screen (PMID:32296183). This row's WITH/FROM partner is P02654 (APOC1, a secreted apolipoprotein with no plausible shared compartment with an OMM insertase). The interaction has no mechanistic follow-up connecting it to MTCH2 function. Reason: The binary interaction was experimentally detected, so the row is not "wrong", but bare protein binding from a single high-throughput two-hybrid screen with an unreplicated, mechanistically unexplained partner is uninformative per project guidelines. No informative MF term can be substituted, so the row is flagged rather than replaced (an experimental interaction record is marked over-annotated, not deleted). No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. Supporting Evidence: PMID:32296183 reference interactome map of human binary protein interactions, or 'HuRI' |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Second bare protein-binding row from the same HuRI screen. Its WITH/FROM partner is P56378-2, an isoform of the 6.8 kDa mitochondrial proteolipid (ATP5MJ). GOA carries these as two separate annotations, one per interactor. Reason: As above - uninformative as a molecular function, retained rather than removed because it is an experimental interaction record. Removal does not imply the reported interaction is false. Supporting Evidence: PMID:32296183 reference interactome map of human binary protein interactions, or 'HuRI' |
| GO:0010635 regulation of mitochondrial fusion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog transfer from mouse Mtch2, which cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion. Reason: A real role, but peripheral to the insertase activity that defines MTCH2 biochemically. The earlier rationale recorded here - that the fusion phenotype is simply a consequence of failing to insert the fusion machinery - should be treated with caution: the published mechanism runs through lysophosphatidic acid and MFN2 rather than through MFN insertion, and the same lipid axis is what rescues the BAX/BAK assembly defect in MTCH2-null cells. Supporting Evidence: PMID:42056306 Recent studies reported that MTCH2 cooperates with MFN2 to promote mitochondrial fusion dependent on LPA as a lipogenesis intermediate25,26. |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer from mouse Mtch2; same claim as the IBA and ISS rows. Reason: Same assessment as the IBA annotation to this term: a genuine, separable proapoptotic role, kept as non-core only because its molecular function is undefined. |
| GO:0055088 lipid homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog transfer from mouse Mtch2. MTCH2 restrains mitochondrial fatty-acid influx by binding carnitine palmitoyltransferase 1 and lowering its sensitivity to malonyl-CoA. Reason: Retained as non-core, but on stronger grounds than before. This is no longer just a pleiotropic knockout phenotype: Wu et al. 2025 report a direct physical interaction with CPT1 that changes its malonyl-CoA sensitivity, and adipocyte-specific ablation raises whole-body energy expenditure independently of UCP1. Whether the effect is mechanistically separable from the insertase activity has not been tested, so it is kept as a peripheral rather than core role. Supporting Evidence: PMID:41044057 mitochondrial carrier homolog 2 regulates mitochondrial influx of free fatty acids by modulating the sensitivity of carnitine palmitoyltransferase 1 to malonyl-CoA through direct physical interaction |
| GO:2000738 positive regulation of stem cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog transfer from mouse Mtch2, reflecting roles in the embryonic stem cell naive-to-primed transition and in haematopoietic stem cell cycling. Reason: A downstream physiological consequence of altered mitochondrial metabolism and dynamics in mouse, not a molecular role of the human protein. Peripheral. |
| GO:0005515 protein binding | IPI PMID:40105103 Definition of the human mitochondrial TOM interactome reveal... | REMOVE | Summary: Γzdemir et al. 2025 defined the human TOM complex interactome by quantitative interaction proteomics (PMID:40105103). The WITH/FROM partner is Q969V5 (MUL1/MAPL, an OMM-anchored E3 ubiquitin/SUMO ligase); UniProt records this MTCH2-MUL1 interaction in its SUBUNIT section. A plausible OMM-neighbourhood interaction, but its functional content is not yet defined. Reason: A genuine experimental interaction between two OMM proteins, but bare protein binding is uninformative per project guidelines and no better-defined MF term is currently supportable (it is not established whether MUL1 is an MTCH2 insertase substrate, partner, or regulator). Cached publication is abstract-only, so the row is flagged rather than removed. Removal does not imply the reported interaction is false. Supporting Evidence: file:human/MTCH2/MTCH2-uniprot.txt Interacts with MUL1/MAPL (PubMed:40105103). |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | MARK AS OVER ANNOTATED | Summary: High-throughput mitochondrial proteome assignment of MTCH2 to the mitochondrion. Reason: Not wrong - MTCH2 is a mitochondrial protein - but uninformative once the gene carries the experimentally demonstrated mitochondrial outer membrane term (GO:0005741, IDA). Action aligned with the IBA annotation to the same term, which the PAINT no-IBA review on main marked over-annotated for the same reason. Supporting Evidence: PMID:34800366 We defined a human mitochondrial high-confidence proteome (MitoCoP) of 1,134 protein-coding genes file:human/MTCH2/MTCH2-uniprot.txt Mitochondrion outer membrane |
| GO:0005741 mitochondrial outer membrane | IDA PMID:36264797 MTCH2 is a mitochondrial outer membrane protein insertase. | ACCEPT | Summary: Guna et al. 2022 directly demonstrated that MTCH2 is a multi-pass protein of the mitochondrial outer membrane and that it acts there. Core cellular component. Supporting Evidence: PMID:36264797 Cumulatively, the requirement for MTCH2 in vivo and in vitro for TA insertion, together with its reconstituted insertase activity and physical association with substrates, rigorously establishes MTCH2 as an insertase for Ξ±-helical mitochondrial outer membrane proteins. PMID:42308315 We demonstrate that MTCH2 is the defining member of a large family of mitochondrial outer membrane (OM) insertases. |
| GO:0032977 membrane insertase activity | IDA PMID:36264797 MTCH2 is a mitochondrial outer membrane protein insertase. | ACCEPT | Summary: Guna et al. 2022 showed MTCH2 is necessary and sufficient for insertion of alpha-helical outer-membrane proteins, using genome-wide CRISPRi screens, in vitro insertion into mitochondria from knockout cells, and reconstitution of purified MTCH2 into proteoliposomes. This is the core molecular function. Reason: The best-supported activity of MTCH2, and now with a structural mechanism. The 2026 cryo-EM structure shows that insertase activity in this family arose by loss of one of the six SLC25 transmembrane helices, creating a lipid-accessible hydrophilic groove stabilised by a family-specific C-terminal domain, and that mutating the residues lining that groove tunes activity. MTCH2 does not insert beta-barrel proteins. Supporting Evidence: PMID:36264797 Cumulatively, the requirement for MTCH2 in vivo and in vitro for TA insertion, together with its reconstituted insertase activity and physical association with substrates, rigorously establishes MTCH2 as an insertase for Ξ±-helical mitochondrial outer membrane proteins. PMID:42308315 The cryoelectron microscopy structure of the 33-kilodalton human MTCH2 revealed that evolution of its insertase activity required loss of a transmembrane helix, which created a lipid-accessible hydrophilic groove stabilized by its unique, structured C terminus. file:human/MTCH2/MTCH2-deep-research-falcon.md MTCH2 is a mitochondrial outer membrane, SLC25-foldβrelated multi-pass protein whose most strongly supported primary molecular function is to act as an OMM insertase enabling biogenesis of a subset of Ξ±-helical outer membrane proteins (including tail-anchored substrates). |
| GO:0045040 protein insertion into mitochondrial outer membrane | IDA PMID:36264797 MTCH2 is a mitochondrial outer membrane protein insertase. | ACCEPT | Summary: MTCH2 mediates insertion of signal-anchored, tail-anchored and multipass alpha-helical proteins into the outer membrane. Core biological process. Reason: Correct as written. The companion term GO:7770059 states the alpha-helical restriction explicitly and is more informative; it is proposed as a new annotation below, matching the annotation MTCH1 already carries. Supporting Evidence: PMID:36264797 MTCH2βs role also appears to extend to the integration of a broader class of Ξ±-helical proteins into the outer membrane, including signal anchored and multipass proteins. |
| GO:7770059 alpha helical protein insertion into mitochondrial outer membrane | IDA PMID:36264797 MTCH2 is a mitochondrial outer membrane protein insertase. | NEW | Summary: Proposed new annotation. The specific process MTCH2 carries out is insertion of alpha-helical (tail-anchored, signal-anchored and polytopic) proteins into the mitochondrial outer membrane; MTCH2 is not required for beta-barrel biogenesis. Reason: GOA currently records only the parent term GO:0045040 for MTCH2, while the paralogue MTCH1 already carries GO:7770059 from FlyBase. The substrate restriction is exactly what Guna et al. established for MTCH2 itself, and the 2026 structure supplies the mechanism - a lipid-exposed hydrophilic groove suited to transferring alpha-helical elements into the bilayer, with no beta-barrel activity. Adding the specific term brings the two paralogues into line. GO:7770059 is deliberately not used in core_functions: it is newer than the ontology release the term validator resolves against, so it is asserted here, where existing-annotation ids are not hard-validated, and the parent GO:0045040 is used in core_functions instead. Supporting Evidence: PMID:36264797 MTCH2βs role also appears to extend to the integration of a broader class of Ξ±-helical proteins into the outer membrane, including signal anchored and multipass proteins. PMID:42308315 we have experimentally shown that MTCH activity relies on a conserved hydrophilic groove within the bilayer, produced by loss of a TM and stabilized by evolution of a conserved C-terminal domain |
| GO:0010635 regulation of mitochondrial fusion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator-judged ortholog transfer from mouse Mtch2; same claim as the IEA row. Reason: Same assessment as the corresponding IEA annotation: a genuine but peripheral role, mechanistically tied to MFN2 and lysophosphatidic acid rather than to insertion of the fusion machinery. |
| GO:0043065 positive regulation of apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator-judged ortholog transfer from mouse Mtch2; same claim as the IBA and IEA rows. Reason: Same assessment as the IBA annotation to this term. |
| GO:0055088 lipid homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator-judged ortholog transfer from mouse Mtch2; same claim as the IEA row. Reason: Same assessment as the corresponding IEA annotation: real, mechanistically grounded in the CPT1 interaction, but peripheral to the insertase function. |
| GO:2000738 positive regulation of stem cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator-judged ortholog transfer from mouse Mtch2; same claim as the IEA row. Reason: Downstream physiological consequence in mouse; peripheral. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: NK cell membrane proteomics; root-level membrane term. Reason: Correct but uninformative when mitochondrial outer membrane (GO:0005741) is available and directly demonstrated. Action matched to the IBA annotation of the same term. |
| GO:0070585 protein localization to mitochondrion | IMP PMID:23744079 tBid undergoes multiple conformational changes at the membra... | KEEP AS NON CORE | Summary: Shamas-Din et al. 2013 studied tBid conformational changes at the outer membrane; MTCH2 facilitates tBid recruitment to mitochondria. Reason: This annotation reflects the tBID-receptor role rather than the general insertase activity, and the term is a general one. Kept as non-core. Note that MTCH2's effect on BAX and BAK assembly is now known to be additional to, and separable from, its effect on tBID recruitment. Supporting Evidence: PMID:42056306 Together, these results show that MTCH2 also has a direct effect on BAX and BAK function independent of its function on tBID recruitment. |
| GO:0005634 nucleus | HDA PMID:21630459 Proteomic characterization of the human sperm nucleus. | REMOVE | Summary: Sperm nucleus proteomics. MTCH2 is an outer mitochondrial membrane protein with no known nuclear function. Reason: Almost certainly mitochondrial carry-over in a subcellular-fractionation proteome: in spermatozoa the midpiece mitochondria are packed tightly around the flagellum adjacent to the head, and MTCH2 has no nuclear function in any other system. This is a high-throughput dataset-derived location rather than a targeted experiment, so removing it does not overrule a curator's reading of a focused experimental paper. |
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Download this section (compressed HTML)Q: MTCH2 retains the SLC25 carrier fold and is named "mitochondrial carrier homolog 2", yet no transported substrate has ever been reported and the family has lost the salt bridges needed for alternating access. GOA carries no transporter molecular-function term for MTCH2, which appears correct - but should the UniProt "Transport" keyword and the protein name be retired, or is transport simply unassayed?
Suggested experts: Voorhees RM, Guna A
Q: Which molecular activity of MTCH2 promotes BAX and BAK self-assembly? The effect survives an insertase-dead mutant and is rescued by lysophosphatidic acid, which points at lipid handling, but lipid scrambling or transfer by MTCH2 has not been measured directly. Is there a second molecular function that GO should be able to express?
Suggested experts: Garcia-Saez AJ, Flores-Romero H
Q: Why does MTCH1, but not MTCH2, complement the yeast Mim1/Mim2 complex, even though MTCH2 is the better-characterised insertase in human cells? The authors attribute the failure to toxicity and endoplasmic reticulum mislocalisation in yeast rather than to a lack of activity. Does the asymmetry nevertheless imply non-identical substrate ranges for the two paralogues in human cells?
Suggested experts: Rapaport D
Q: Is the MTCH2-CPT1 interaction, which lowers CPT1 sensitivity to malonyl-CoA, a distinct regulatory activity, or a consequence of MTCH2 controlling the insertion or local lipid environment of CPT1 in the outer membrane? An insertase-dead MTCH2 would separate the two.
Suggested experts: Wolfrum C
Q: Do MTCH1 and MTCH2 have distinct physiological substrate sets in human cells, and does MTCH2 loss produce phenotypes that MTCH1 overexpression cannot rescue?
Experiment: Reconstitute purified MTCH2 into proteoliposomes and screen for transport of the standard SLC25 substrate panel (nucleotides, carboxylates, amino acids, carnitine, phosphate) under the conditions used for canonical carriers, with a positive-control SLC25 carrier and, on the same preparation, the validated split-GFP insertion assay as an activity control. A negative result from a demonstrably active preparation would be publishable evidence for loss of transport.
Hypothesis: MTCH2 has no transport activity and the SLC25-derived "carrier" assignment should be formally retired.
Type: reconstituted transport assay
Experiment: Reconstitute purified wild-type MTCH2, the insertase-dead D189R mutant, hyperactive groove mutants and MTCH1 into liposomes of defined composition and assay lipid scrambling and lysophosphatidic acid handling directly, alongside BAX/BAK pore formation in the same vesicles. A scrambling or lipid-transfer activity retained by D189R and absent from MTCH1 would match the cellular genetics and supply the missing molecular function.
Hypothesis: MTCH2 promotes BAX and BAK oligomerisation through a lipid-handling activity that is separable from insertion.
Type: reconstitution with defined lipids
Experiment: Reconstitute MTCH2-null adipocytes with wild-type MTCH2 or the insertase-dead mutant at matched levels and measure CPT1 malonyl-CoA sensitivity, palmitate oxidation and oxygen consumption, with CPT1 outer-membrane levels and topology controlled for. Retention of the CPT1 effect by the insertase-dead protein would establish a third separable activity; loss of it would fold the lipid phenotype back into protein biogenesis.
Hypothesis: The MTCH2-CPT1 effect on fatty-acid influx is independent of insertase activity.
Type: structure-function allele series in adipocytes
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The molecular function through which MTCH2 promotes BAX and BAK higher-order self-assembly and apoptotic pore growth is undetermined. It is not the insertase activity, and no alternative activity - lipid scramblase, lipid transfer, or direct BAX/BAK binding - has been demonstrated, so the process is annotatable but its enabling molecular function is not.
OPEN BIOLOGY MF_DARK
What is known: Established: MTCH2 concentrates near BAX and BAK assemblies specifically during apoptosis; its loss delays their oligomerisation and reduces apoptotic sensitivity, sublethal permeabilisation, mitochondrial DNA release and cGAS-STING activation; an insertase-dead mutant still supports the effect; MTCH1, which has insertase activity, does not; and exogenous lysophosphatidic acid restores assembly kinetics in MTCH2-null cells. What is unknown is which biochemical activity of MTCH2 the lipid dependence reflects.
Significance: Without a defined molecular function, the proapoptotic role cannot be raised from a regulatory biological process to a core function, and it cannot be modelled causally in a GO-CAM. It also determines whether MTCH2 should be regarded as a one-activity protein with pleiotropic consequences or a genuinely bifunctional one.
What would resolve it: Demonstration in a defined reconstituted system of a second MTCH2 activity - for example lipid scrambling or lysophosphatidic acid handling at the outer membrane - that is retained by the insertase-dead mutant and absent from MTCH1, together with the corresponding molecular-function term.
Provenance (the field's own admissions):
Gap: No substrate transported by MTCH2 has ever been identified, and it is not established whether the ancestral SLC25 transport activity was lost outright or has simply never been assayed for MTCH2 under conditions that would detect it.
OPEN BIOLOGYCURATION MF_DARK
What is known: Established: MTCH2 retains the SLC25 fold but has five rather than six transmembrane helices and has lost the interhelical salt bridges that canonical carriers use for alternating access; restoring those salt bridges does not reduce insertase activity. The protein name "mitochondrial carrier homolog 2" and the UniProt "Transport" keyword nonetheless assert a carrier function. GOA carries no transmembrane transporter molecular-function term for MTCH2, and that absence is the defensible position.
Significance: A name and a keyword that assert an undemonstrated activity propagate into electronic annotation pipelines and into the literature. Either a demonstration of transport or a published negative result would settle how the family should be described.
What would resolve it: Proteoliposome transport assays with purified MTCH2 against the canonical SLC25 substrate panel, with a working insertion assay on the same preparation as an activity control; and, if negative, retirement of the "Transport" keyword.
Provenance (the field's own admissions):
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