Mitochondrial outer membrane protein insertase that mediates insertion of alpha-helical transmembrane proteins (signal-anchored, tail-anchored, and multi-pass) into the outer membrane. Identified by Guna et al. 2022 as the metazoan functional equivalent of the yeast Mim1/Mim2 complex, despite no sequence homology. Uses a diverged solute carrier fold. Does not insert beta-barrel proteins (handled by SAM/SAMM50). Also implicated in apoptosis (tBID receptor), mitochondrial fusion, lipid homeostasis, and stem cell biology, but the core evolved function is as an outer membrane insertase.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005739
mitochondrion
|
IBA
GO_REF:0000033 |
MARK AS OVER ANNOTATED |
Summary: Too general — MTCH2 specifically localizes to the mitochondrial outer membrane (PMID:36264797).
Reason: Subsumed by mitochondrial outer membrane annotation.
|
|
GO:0016020
membrane
|
IBA
GO_REF:0000033 |
MARK AS OVER ANNOTATED |
Summary: Extremely generic. MTCH2 is a multi-pass OM protein.
Reason: Subsumed by mitochondrial outer membrane.
|
|
GO:0043065
positive regulation of apoptotic process
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: MTCH2 acts as tBID receptor at the OM, facilitating BAX/BAK activation. This is a well-characterized secondary function, but the core evolved function is as an insertase. Apoptotic role may be secondary to its insertase activity.
Reason: Secondary function; the insertase role is core.
|
|
GO:0005741
mitochondrial outer membrane
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Correct. MTCH2 is a multi-pass protein of the mitochondrial outer membrane. Directly demonstrated (PMID:36264797).
Supporting Evidence:
file:human/MTCH2/MTCH2-deep-research-falcon.md
Falcon synthesis supports MTCH2 as an integral mitochondrial outer membrane protein with carrier-fold-related topology.
|
|
GO:0070585
protein localization to mitochondrion
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: MTCH2 mediates insertion of proteins into the OM, which could be considered protein localization. However the more specific insertase terms are more informative.
Reason: Generic; the specific insertase annotation is more informative.
|
|
GO:0005515
protein binding
|
IPI
PMID:32296183 A reference map of the human binary protein interactome. |
REMOVE |
Summary: HuRI binary interactome screen. Protein binding is uninformative.
Reason: Protein binding is uninformative per guidelines.
|
|
GO:0010635
regulation of mitochondrial fusion
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Mouse MTCH2 KO affects mitochondrial fusion (Bahat et al.). This may be secondary to insertase function — fusion machinery (MFN1/2) requires OM insertion. Non-core pleiotropic effect.
Reason: Likely downstream of insertase function affecting fusion machinery insertion.
|
|
GO:0043065
positive regulation of apoptotic process
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Ensembl Compara transfer. Redundant with IBA. Non-core function.
Reason: Secondary function; insertase role is core.
|
|
GO:0055088
lipid homeostasis
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Mouse studies showed MTCH2 role in adipocyte differentiation and lipid metabolism. Pleiotropic effect, likely downstream of insertase function.
Reason: Pleiotropic downstream effect.
|
|
GO:2000738
positive regulation of stem cell differentiation
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Mouse studies showed MTCH2 role in ESC naive-to-primed transition and HSC cycling. Pleiotropic effect.
Reason: Pleiotropic downstream effect of insertase function.
|
|
GO:0005515
protein binding
|
IPI
PMID:40105103 Definition of the human mitochondrial TOM interactome reveal... |
REMOVE |
Summary: Oezdemir et al. 2025 defined TOM interactome, found MTCH2 interaction. Protein binding uninformative.
Reason: Protein binding uninformative per guidelines.
|
|
GO:0005739
mitochondrion
|
HTP
PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... |
MARK AS OVER ANNOTATED |
Summary: HTP proteome confirms mitochondrial localization. Too general.
Reason: Subsumed by mitochondrial outer membrane annotation.
|
|
GO:0005741
mitochondrial outer membrane
|
IDA
PMID:36264797 MTCH2 is a mitochondrial outer membrane protein insertase. |
ACCEPT |
Summary: Guna et al. 2022 directly demonstrated MTCH2 is a multi-pass protein of the mitochondrial outer membrane. Core CC annotation from the landmark insertase paper.
Supporting Evidence:
PMID:36264797
MTCH2 is a mitochondrial outer membrane protein insertase.
file:human/MTCH2/MTCH2-deep-research-falcon.md
Falcon synthesis identifies MTCH2 as an integral OMM insertase for alpha-helical mitochondrial outer membrane substrates.
|
|
GO:0032977
membrane insertase activity
|
IDA
PMID:36264797 MTCH2 is a mitochondrial outer membrane protein insertase. |
ACCEPT |
Summary: Guna et al. 2022 demonstrated MTCH2 is both necessary and sufficient for insertion of alpha-helical OM proteins using CRISPR screens and reconstitution assays. This is the core molecular function of MTCH2.
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 α-helical mitochondrial outer membrane proteins.
file:human/MTCH2/MTCH2-deep-research-falcon.md
Falcon synthesis supports membrane insertase activity as the most strongly supported primary molecular function of MTCH2.
|
|
GO:0045040
protein insertion into mitochondrial outer membrane
|
IDA
PMID:36264797 MTCH2 is a mitochondrial outer membrane protein insertase. |
ACCEPT |
Summary: Guna et al. 2022 showed MTCH2 mediates insertion of signal-anchored, tail-anchored, and multi-pass alpha-helical proteins into the OM. Core BP.
Supporting Evidence:
PMID:36264797
MTCH2’s role also appears to extend to the integration of a broader class of α-helical proteins into the outer membrane, including signal anchored and multipass proteins.
file:human/MTCH2/MTCH2-deep-research-falcon.md
Falcon synthesis supports protein insertion into the mitochondrial outer membrane as the core MTCH2 biological process.
|
|
GO:0010635
regulation of mitochondrial fusion
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Ortholog-based transfer from mouse. Non-core pleiotropic effect.
Reason: Downstream of insertase function.
|
|
GO:0043065
positive regulation of apoptotic process
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Ortholog transfer. Non-core, redundant with IBA and IEA.
Reason: Secondary function.
|
|
GO:0055088
lipid homeostasis
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Ortholog transfer. Non-core pleiotropic effect.
Reason: Pleiotropic downstream effect.
|
|
GO:2000738
positive regulation of stem cell differentiation
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Ortholog transfer. Non-core pleiotropic effect.
Reason: Pleiotropic downstream effect.
|
|
GO:0016020
membrane
|
HDA
PMID:19946888 Defining the membrane proteome of NK cells. |
MARK AS OVER ANNOTATED |
Summary: NK cell membrane proteomics. Extremely generic.
Reason: Subsumed by mitochondrial outer membrane.
|
|
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 OM. MTCH2 facilitates tBid recruitment to mitochondria, which is part of its apoptotic function. Non-core.
Reason: Reflects apoptotic tBid receptor function, not core insertase activity.
|
|
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. Nuclear localization in sperm is likely an artifact of sperm ultrastructure where mitochondria wrap the midpiece close to the nucleus.
Reason: Likely artifact. MTCH2 is a mitochondrial outer membrane protein with no known nuclear function.
|
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The literature synthesized here explicitly matches the UniProt target: human MTCH2 (Q9Y6C9), also termed MIMP/HSPC032, described as a mitochondrial outer membrane (OMM), mitochondrial-carrier/SLC25-fold–related protein (i.e., mitochondrial carrier homolog) (guna2022mtch2isa pages 1-3, schwarz2007mitochondrialcarriersand pages 4-5, guna2022mtch2isa pages 3-4). No evidence in the retrieved corpus indicates a different gene/protein with a confusingly similar symbol being substituted.
Historically, MTCH2 was recognized as a mitochondrial carrier family homolog but unusual in that it is exposed on the mitochondrial surface and likely spans the outer mitochondrial membrane rather than the inner membrane where canonical SLC25 carriers reside (schwarz2007mitochondrialcarriersand pages 4-5). Fold-recognition and later structural modeling support a carrier-like multi-pass helical fold (SLC25-like) but diverged from canonical transporters (schwarz2007mitochondrialcarriersand pages 4-5, guna2022mtch2isa pages 3-4).
Tail-anchored proteins are α-helical membrane proteins with a C-terminal transmembrane helix that are inserted post-translationally. An insertase is a membrane protein that catalyzes/assists insertion of such substrates into a target membrane (guna2022mtch2isa pages 1-3). MTCH2 is now best supported as an OMM insertase for a subset of α-helical OMM proteins (guna2022mtch2isa pages 1-3, guna2022mtch2isa pages 9-14).
A pivotal mechanistic study (Guna et al., Science, publication month/year Oct 2022, URL: https://doi.org/10.1126/science.add1856) established that MTCH2 is necessary and sufficient for insertion/biogenesis of diverse α-helical OMM proteins, including tail-anchored, signal-anchored, and some multipass proteins, while not being required for β-barrel OMM protein biogenesis (guna2022mtch2isa pages 1-3, guna2022mtch2isa pages 3-4).
Key experimental support includes:
- Genome-wide CRISPRi and split-GFP insertion reporters showing MTCH2 dependence for OMM substrate integration (guna2022mtch2isa pages 1-3, guna2022mtch2isa pages 9-14).
- In vitro insertion assays with mitochondria from MTCH2 knockout cells showing reduced insertion of MTCH2-dependent substrates and rescue by MTCH2 re-expression (guna2022mtch2isa pages 9-14).
- Purified MTCH2 reconstitution into proteoliposomes where MTCH2 alone is sufficient to catalyze insertion of MTCH2-dependent substrates (protease protection assays) (guna2022mtch2isa pages 9-14, guna2022mtch2isa pages 14-16).
- Mechanistic mapping suggesting a membrane-accessible hydrophilic groove and critical intramembrane polar/charged residues; mutational changes can reduce or enhance insertase activity (guna2022mtch2isa pages 14-16, guna2022mtch2isa pages 3-4).
Figure-based evidence:
- A schematic of the split-GFP reporter logic used to quantify insertion is shown in the retrieved figure panel (guna2022mtch2isa media a883b91c).
- Reconstituted proteoliposome insertion/protease-protection evidence for MTCH2-dependent substrates is shown in the retrieved panel (guna2022mtch2isa media 6f107e97).
Functional consequence: MTCH2 insertase activity can modulate apoptosis sensitivity in leukemia cells (e.g., Annexin-V apoptosis readout after imatinib 1 μM for 72 h in K562 cells, dependent on insertase-activity mutants) (guna2022mtch2isa pages 14-16).
Interpretation: In contrast to classical SLC25 carriers (metabolite transporters in the inner mitochondrial membrane), the strongest experimental support indicates MTCH2’s primary biochemical role is protein insertion/topogenesis in the OMM rather than small-molecule transport (guna2022mtch2isa pages 1-3, guna2022mtch2isa pages 14-16).
Earlier work and mechanistic syntheses describe MTCH2 as an OMM protein that interacts with BID/tBID and facilitates recruitment of tBID to mitochondria, promoting efficient BAX/BAK-mediated mitochondrial apoptosis (schwarz2007mitochondrialcarriersand pages 4-5). The current framing in mechanistic commentary remains that MTCH2 participates as an OMM receptor/platform for BID-family pro-apoptotic signaling, though lipid components (e.g., cardiolipin) can provide alternative recruitment routes in some contexts (schwarz2007mitochondrialcarriersand pages 4-5).
Expert synthesis (evolution/role framing): A 2024 mechanistic perspective (Gross, Jan 2024, URL: https://doi.org/10.26124/bec:2024-0001) emphasizes MTCH2 as a non-classical carrier-like OMM protein with “day job” (insertase) and “night job” (BID-associated apoptosis regulation), integrating evidence that MTCH2 forms prominent complexes with BID and may influence BID/tBID insertion/engagement at mitochondria (gross2024abidmtch2love pages 5-7).
A major 2023–2024 development is a mechanistic dissection of MTCH2’s role in mitochondrial fusion.
Goldman et al. (EMBO Reports, Dec 2023, URL: https://doi.org/10.1038/s44319-023-00009-1) show:
- MTCH2 loss causes mitochondrial fragmentation, while MTCH2 overexpression drives mitochondrial elongation (goldman2023mtch2cooperateswith pages 6-8).
- Two partially redundant fusion-supporting mechanisms: (i) an OMM mechanism requiring MTCH2 and MFN1 and (ii) an ER/MAM-linked mechanism requiring MFN2 and de novo lysophosphatidic acid (LPA) synthesis (goldman2023mtch2cooperateswith pages 1-2).
- MFN2-dependent rescue of MTCH2 KO morphology is sensitive to LPA synthesis inhibition/silencing, while MTCH2 overexpression can enforce elongation even under GPAT inhibition conditions used in the study (e.g., FSG67 100 μM for 16 h) (goldman2023mtch2cooperateswith pages 6-8).
- The paper reports explicit sampling/statistics in morphology scoring (e.g., ≥25 cells per genotype in some analyses; ≥30 fields/condition in others; one-way ANOVA with thresholds up to P < 0.001*), and also notes a readout where MTCH2 overexpression induced hyperfusion in ~20%** of WT and MTCH2 KO cells in a specific experimental context (goldman2023mtch2cooperateswith pages 1-2, goldman2023mtch2cooperateswith pages 6-8).
Interpretation: These data support MTCH2 as a mediator of mitochondrial fusion capacity/plasticity, mechanistically tied to lipid metabolism at ER–mitochondria interfaces rather than simply altering abundance of canonical fission/fusion proteins (goldman2023mtch2cooperateswith pages 1-2).
A 2024 study proposes that lipid scrambling is a general feature of protein insertases, explicitly discussing MTCH2 as a representative human mitochondrial insertase (Li et al., PNAS, Apr 2024, URL: https://doi.org/10.1073/pnas.2319476121) (guo2025mtch2inregulation pages 4-4). In parallel, expert synthesis highlights independent evidence suggesting MTCH2 may act as a lipid scramblase in vitro/simulation and posits this as a plausible mechanistic bridge between MTCH2’s roles in membrane remodeling, lipid handling, and mitochondrial dynamics (gross2024abidmtch2love pages 5-7).
Caveat: In the retrieved evidence here, scrambling is best treated as supportive/emerging rather than fully established as MTCH2’s dominant in vivo biochemical function (gross2024abidmtch2love pages 5-7, guo2025mtch2inregulation pages 4-4).
Across mechanistic sources, MTCH2 is localized to the mitochondrial outer membrane (guna2022mtch2isa pages 1-3, schwarz2007mitochondrialcarriersand pages 4-5, gross2024abidmtch2love pages 5-7). Its most directly demonstrated activities—protein insertion of α-helical OMM proteins and modulation of OMM proteostasis/TA mistargeting—occur at the OMM (guna2022mtch2isa pages 1-3, guna2022mtch2isa pages 3-4). The fusion pathway evidence further implies MTCH2’s functional coupling to ER–mitochondria contact site lipid metabolism (MAM) via MFN2/LPA synthesis (goldman2023mtch2cooperateswith pages 1-2).
Goldman et al. provide a mechanistic model in which MTCH2 supports fusion in a pathway redundant with MFN2/LPA synthesis, helping maintain mitochondrial plasticity during stress (Dec 2023) (goldman2023mtch2cooperateswith pages 1-2, goldman2023mtch2cooperateswith pages 6-8).
Li et al. (Apr 2024) argue insertases frequently have lipid scrambling capability, offering a conceptual framework potentially unifying MTCH2’s protein biogenesis role with lipid/morphology phenotypes (guo2025mtch2inregulation pages 4-4).
A 2024 review (Peng et al., Drug Design, Development and Therapy, Jun 2024, URL: https://doi.org/10.2147/DDDT.S460448) summarizes MTCH2’s roles across apoptosis, metabolism (glycolysis/OXPHOS shifts), mitochondrial dynamics, development, cancers, and neurodegenerative disease contexts, emphasizing mitochondrial function as a common denominator (peng2024mtch2inmetabolic pages 10-11, peng2024mtch2inmetabolic pages 6-7).
Sun et al. (Oncology Letters, Aug 2024, URL: https://doi.org/10.3892/ol.2024.14625) analyzed 67 high-grade serous ovarian cancer patients, reporting increased MTCH2 (and AIMP2/claudin-3) in tumors versus adjacent tissues and associating MTCH2 with clinical/pathological features (e.g., FIGO stage, differentiation), alongside in vitro knockdown experiments suggesting effects on ATP production, mitochondrial dysfunction, migration/invasion, and apoptosis (peng2024mtch2inmetabolic pages 6-7).
Because MTCH2 controls biogenesis of specific OMM proteins and influences apoptosis sensitivity in leukemia cells (e.g., imatinib challenge assays dependent on MTCH2 activity), MTCH2 is a plausible point of intervention for modulating OMM proteostasis–apoptosis coupling (guna2022mtch2isa pages 14-16, guna2022mtch2isa pages 1-3). At present, this is an active research direction rather than a deployed therapy.
The 2023 fusion mechanism positions MTCH2 within a lipid-metabolic control layer (LPA synthesis; MFN2 at ER/MAM) that is broadly implicated in metabolic disease and stress adaptation, suggesting potential indirect intervention opportunities (e.g., lipid synthesis enzymes) while MTCH2-targeted therapeutics remain exploratory (goldman2023mtch2cooperateswith pages 1-2).
Recent cancer-context studies (e.g., ovarian cancer cohort analysis) and integrative reviews support MTCH2 as a candidate biomarker/target, but clinical deployment is not yet established; the evidence base is currently preclinical/observational and context-dependent (peng2024mtch2inmetabolic pages 6-7, peng2024mtch2inmetabolic pages 10-11).
The following table summarizes MTCH2 functional claims, evidence types, and the most relevant 2022–2024 sources.
| Function/Process | Mechanistic description | Key experimental evidence (assay/model) | Key quantitative/statistical details (if available) | Key sources (with year, journal, URL) |
|---|---|---|---|---|
| OMM protein insertase for tail-anchored and other α-helical proteins | Human MTCH2 (UniProt Q9Y6C9; MIMP/HSPC032) is an integral mitochondrial outer membrane protein that has co-opted the SLC25-like carrier fold to insert selected α-helical OMM proteins, including tail-anchored, signal-anchored, and some multipass substrates; activity depends on intramembrane hydrophilic/polar residues and helps prevent ER mistargeting of mitochondrial substrates (guna2022mtch2isa pages 4-6, guna2022mtch2isa pages 9-14, guna2022mtch2isa pages 14-16, guna2022mtch2isa pages 3-4, guna2022mtch2isa pages 1-3, guna2022mtch2isa media a883b91c) | Genome-wide CRISPRi split-GFP reporter screens for OMP25 integration; quantitative mitochondrial proteomics; in vitro insertion of radiolabeled substrates into mitochondria from MTCH2-KO cells; site-specific photocrosslinking to nascent substrates; purified MTCH2 reconstituted into proteoliposomes sufficient for substrate insertion; mutational analysis of charged residues in the membrane (guna2022mtch2isa pages 9-14, guna2022mtch2isa pages 14-16, guna2022mtch2isa pages 1-3, guna2022mtch2isa media a883b91c) | Rescue tested across 3 biological replicates in vitro; mass spectrometry changes assessed across 4 biological replicates; apoptosis sensitization in K562 measured after imatinib 1 μM for 72 h by Annexin-V; screen identified MTCH2 as causing the strongest loss of OMP25 reporter integration among hits discussed (guna2022mtch2isa pages 9-14, guna2022mtch2isa pages 14-16, guna2022mtch2isa pages 1-3) | Guna et al., 2022, Science, https://doi.org/10.1126/science.add1856; Kizmaz & Herrmann, 2023, J Cell Sci, https://doi.org/10.1242/jcs.261219 (guna2022mtch2isa pages 4-6, guna2022mtch2isa pages 9-14, guna2022mtch2isa pages 14-16, guna2022mtch2isa pages 1-3) |
| Facilitator/receptor for tBID recruitment and mitochondrial apoptosis | Before the insertase role was established, MTCH2 was identified as an OMM-exposed protein that facilitates recruitment of tBID/BID to mitochondria and promotes efficient BAX-dependent mitochondrial apoptosis; current view is that MTCH2 contributes as a protein/lipid-interaction platform rather than acting as a canonical transporter, and cardiolipin can partly compensate in some contexts (schwarz2007mitochondrialcarriersand pages 4-5, gross2024abidmtch2love pages 5-7) | Crosslinking of MTCH2–tBID complexes; biochemical identification of MTCH2-containing resident complex recruiting tBID and BAX upon TNFα signaling; knockout/loss-of-function studies showing reduced apoptotic sensitivity; later work showing cardiolipin or MTCH2 can each support tBID recruitment depending on context; mechanistic reviews integrating 2007/2012 evidence (schwarz2007mitochondrialcarriersand pages 4-5, gross2024abidmtch2love pages 5-7) | Historical studies reported a cross-linkable ~45 kDa MTCH2–tBID complex and an ~185 kDa resident mitochondrial complex containing MTCH2 in apoptotic signaling models; quantitative values vary by model and are mainly qualitative in the retrieved evidence (schwarz2007mitochondrialcarriersand pages 4-5) | Zaltsman et al., 2010, Nature Cell Biology, https://doi.org/10.1038/ncb2057; Raemy et al., 2016, Cell Death Differentiation, https://doi.org/10.1038/cdd.2015.166; Schwarz et al., 2007, Apoptosis, https://doi.org/10.1007/s10495-007-0748-2; Robinson et al., 2012, Experimental Cell Research, https://doi.org/10.1016/j.yexcr.2012.01.026 (schwarz2007mitochondrialcarriersand pages 4-5, gross2024abidmtch2love pages 5-7) |
| Cooperation with MFN2 and lysophosphatidic acid (LPA) synthesis to sustain mitochondrial fusion | MTCH2 supports mitochondrial plasticity/fusion through a pathway functionally distinct from, but redundant with, MFN2. MTCH2 can enforce fusion in an MFN1-dependent manner, whereas MFN2-dependent rescue of MTCH2 loss requires de novo LPA synthesis, implicating ER–mitochondria lipid handling/MAM biology rather than altered abundance of core fusion proteins (gross2024abidmtch2love pages 5-7, goldman2023mtch2cooperateswith pages 6-8, goldman2023mtch2cooperateswith pages 1-2) | MTCH2 knockout and overexpression in HEK293T cells and MEFs; mitochondrial morphology scoring; MFN1/MFN2 genetic dependency tests; ER-targeted MFN2 rescue experiments; GPAT inhibition with FSG67 and GPAT3/4 silencing to block LPA synthesis; stress-induced hyperfusion assays (HBSS, cycloheximide) (goldman2023mtch2cooperateswith pages 6-8, goldman2023mtch2cooperateswith pages 1-2) | GPAT inhibitor FSG67 used at 100 μM for 16 h; morphology quantification included at least 25 WT and 25 MTCH2-KO cells and at least 30 fields/condition in cited experiments; statistical testing by one-way ANOVA with SEM and significance thresholds ns, P<0.05, P<0.01, **P<0.001; MTCH2 overexpression induced hyperfusion in ~20% of WT and MTCH2-KO cells in one assay summary (goldman2023mtch2cooperateswith pages 6-8, goldman2023mtch2cooperateswith pages 1-2) | Goldman et al., 2023, EMBO Reports, https://doi.org/10.1038/s44319-023-00009-1 (goldman2023mtch2cooperateswith pages 6-8, goldman2023mtch2cooperateswith pages 1-2) |
| Lipid scrambling associated with insertase function | Recent computational/biophysical work supports the idea that protein insertases, including MTCH2, can also catalyze phospholipid scrambling, offering a possible mechanistic link between MTCH2’s roles in membrane remodeling, fusion, lipid homeostasis, and protein biogenesis; for MTCH2 this remains supportive rather than fully resolved in vivo (gross2024abidmtch2love pages 5-7) | PNAS 2024 combined biochemical and in silico analyses across insertases and included MTCH2 as a representative human mitochondrial insertase; review synthesis connected these findings to MTCH2-dependent lipid handling and membrane dynamics phenotypes (gross2024abidmtch2love pages 5-7) | Retrieved evidence is mechanistic and comparative rather than MTCH2-specific quantitative kinetics in cells; no MTCH2-specific scrambling rate constants were provided in the accessible evidence here (gross2024abidmtch2love pages 5-7) | Li et al., 2024, PNAS, https://doi.org/10.1073/pnas.2319476121; Gross, 2024, Bioenergetics Communications, https://doi.org/10.26124/bec:2024-0001 (gross2024abidmtch2love pages 5-7) |
| Metabolic regulation and nutrient/redox homeostasis | MTCH2 loss shifts cells toward high energy demand, oxidative metabolism, oxidative stress, and broad metabolite depletion, consistent with MTCH2 as a regulator linking mitochondrial morphology, lipid handling, and metabolic state; these findings fit earlier links to obesity/diabetes GWAS and stem-cell metabolic programs (chourasia2023highenergydemandand pages 1-5, peng2024mtch2inmetabolic pages 10-11, peng2024mtch2inmetabolic pages 6-7) | Temporal metabolomics and lipidomics in MTCH2-knockout cells with rescue by MTCH2 re-expression; phenotypic readouts of adipocyte differentiation; review synthesis of stem cell, developmental, and disease literature (chourasia2023highenergydemandand pages 1-5, peng2024mtch2inmetabolic pages 10-11, peng2024mtch2inmetabolic pages 6-7) | Preprint reports increased ATP demand, oxidized environment, depletion of many metabolites, adaptive decrease in membrane lipids and increase in storage lipids; accessible excerpt does not provide effect sizes/p-values. Review notes homozygous Mtch2−/− embryonic lethality at E7.5 and a reported 2.3-fold MTCH2 increase in treated MDA-MB-231 cells from another study (chourasia2023highenergydemandand pages 1-5, peng2024mtch2inmetabolic pages 6-7) | Chourasia et al., 2023, bioRxiv, https://doi.org/10.1101/2023.12.15.571941; Peng et al., 2024, Drug Design, Development and Therapy, https://doi.org/10.2147/DDDT.S460448 (chourasia2023highenergydemandand pages 1-5, peng2024mtch2inmetabolic pages 10-11, peng2024mtch2inmetabolic pages 6-7) |
| Cancer and disease context | MTCH2 expression/function has disease relevance in glioma, ovarian cancer, AML, neurodegeneration, stem-cell fate, and developmental phenotypes. Evidence supports MTCH2 as a context-dependent vulnerability or biomarker candidate, though no approved MTCH2-targeted therapy exists yet (guna2022mtch2isa pages 4-6, chourasia2023highenergydemandand pages 1-5, peng2024mtch2inmetabolic pages 10-11, peng2024mtch2inmetabolic pages 6-7) | 2024 ovarian cancer study measured MTCH2 in patient tumors and manipulated MTCH2 in SK-OV-3 cells; review summarizes glioma/AML/neuronal studies; insertase paper linked MTCH2 activity to apoptosis sensitivity in leukemia cells (guna2022mtch2isa pages 4-6, peng2024mtch2inmetabolic pages 10-11, peng2024mtch2inmetabolic pages 6-7) | Ovarian cancer study analyzed 67 high-grade serous ovarian cancer patients and found increased MTCH2/AIMP2/claudin-3 in tumors vs adjacent tissue, with MTCH2 associated with FIGO stage and differentiation; in vitro MTCH2 knockdown reduced ATP production and increased apoptosis. K562 apoptosis sensitization assay in Science paper used imatinib 1 μM for 72 h (guna2022mtch2isa pages 4-6, peng2024mtch2inmetabolic pages 6-7) | Sun et al., 2024, Oncology Letters, https://doi.org/10.3892/ol.2024.14625; Peng et al., 2024, Drug Design, Development and Therapy, https://doi.org/10.2147/DDDT.S460448; Guna et al., 2022, Science, https://doi.org/10.1126/science.add1856 (guna2022mtch2isa pages 4-6, peng2024mtch2inmetabolic pages 10-11, peng2024mtch2inmetabolic pages 6-7) |
Table: This table summarizes experimentally supported functions of human MTCH2/Q9Y6C9, emphasizing mechanistic evidence, recent 2023-2024 developments, and disease-relevant contexts. It is useful as a compact evidence map separating well-supported core functions from emerging hypotheses.
MTCH2 is a mitochondrial outer membrane, SLC25-fold–related multi-pass protein whose most strongly supported primary molecular function is to act as an OMM insertase enabling biogenesis of a subset of α-helical outer membrane proteins (including tail-anchored substrates). This core activity plausibly connects to its established roles in BID/tBID-associated mitochondrial apoptosis signaling and to newer 2023–2024 mechanisms linking MTCH2 to mitochondrial fusion plasticity through lipid metabolism (LPA synthesis; ER–mitochondria coupling). Lipid scrambling by MTCH2/insertases is an active emerging hypothesis that may unify MTCH2’s protein-biogenesis and membrane-morphology phenotypes but requires additional MTCH2-specific in vivo quantification (guna2022mtch2isa pages 1-3, guna2022mtch2isa pages 9-14, goldman2023mtch2cooperateswith pages 1-2, guo2025mtch2inregulation pages 4-4, schwarz2007mitochondrialcarriersand pages 4-5).
References
(guna2022mtch2isa pages 1-3): Alina Guna, Taylor A. Stevens, Alison J. Inglis, Joseph M. Replogle, Theodore K. Esantsi, Gayathri Muthukumar, Kelly C. L. Shaffer, Maxine L. Wang, Angela N. Pogson, Jeff J. Jones, Brett Lomenick, Tsui-Fen Chou, Jonathan S. Weissman, and Rebecca M. Voorhees. Mtch2 is a mitochondrial outer membrane protein insertase. Science, 378:317-322, Oct 2022. URL: https://doi.org/10.1126/science.add1856, doi:10.1126/science.add1856. This article has 162 citations and is from a highest quality peer-reviewed journal.
(schwarz2007mitochondrialcarriersand pages 4-5): Michal Schwarz, Miguel A. Andrade-Navarro, and Atan Gross. Mitochondrial carriers and pores: key regulators of the mitochondrial apoptotic program? Apoptosis, 12:869-876, Feb 2007. URL: https://doi.org/10.1007/s10495-007-0748-2, doi:10.1007/s10495-007-0748-2. This article has 105 citations and is from a peer-reviewed journal.
(guna2022mtch2isa pages 3-4): Alina Guna, Taylor A. Stevens, Alison J. Inglis, Joseph M. Replogle, Theodore K. Esantsi, Gayathri Muthukumar, Kelly C. L. Shaffer, Maxine L. Wang, Angela N. Pogson, Jeff J. Jones, Brett Lomenick, Tsui-Fen Chou, Jonathan S. Weissman, and Rebecca M. Voorhees. Mtch2 is a mitochondrial outer membrane protein insertase. Science, 378:317-322, Oct 2022. URL: https://doi.org/10.1126/science.add1856, doi:10.1126/science.add1856. This article has 162 citations and is from a highest quality peer-reviewed journal.
(guna2022mtch2isa pages 9-14): Alina Guna, Taylor A. Stevens, Alison J. Inglis, Joseph M. Replogle, Theodore K. Esantsi, Gayathri Muthukumar, Kelly C. L. Shaffer, Maxine L. Wang, Angela N. Pogson, Jeff J. Jones, Brett Lomenick, Tsui-Fen Chou, Jonathan S. Weissman, and Rebecca M. Voorhees. Mtch2 is a mitochondrial outer membrane protein insertase. Science, 378:317-322, Oct 2022. URL: https://doi.org/10.1126/science.add1856, doi:10.1126/science.add1856. This article has 162 citations and is from a highest quality peer-reviewed journal.
(guna2022mtch2isa pages 14-16): Alina Guna, Taylor A. Stevens, Alison J. Inglis, Joseph M. Replogle, Theodore K. Esantsi, Gayathri Muthukumar, Kelly C. L. Shaffer, Maxine L. Wang, Angela N. Pogson, Jeff J. Jones, Brett Lomenick, Tsui-Fen Chou, Jonathan S. Weissman, and Rebecca M. Voorhees. Mtch2 is a mitochondrial outer membrane protein insertase. Science, 378:317-322, Oct 2022. URL: https://doi.org/10.1126/science.add1856, doi:10.1126/science.add1856. This article has 162 citations and is from a highest quality peer-reviewed journal.
(guna2022mtch2isa media a883b91c): Alina Guna, Taylor A. Stevens, Alison J. Inglis, Joseph M. Replogle, Theodore K. Esantsi, Gayathri Muthukumar, Kelly C. L. Shaffer, Maxine L. Wang, Angela N. Pogson, Jeff J. Jones, Brett Lomenick, Tsui-Fen Chou, Jonathan S. Weissman, and Rebecca M. Voorhees. Mtch2 is a mitochondrial outer membrane protein insertase. Science, 378:317-322, Oct 2022. URL: https://doi.org/10.1126/science.add1856, doi:10.1126/science.add1856. This article has 162 citations and is from a highest quality peer-reviewed journal.
(guna2022mtch2isa media 6f107e97): Alina Guna, Taylor A. Stevens, Alison J. Inglis, Joseph M. Replogle, Theodore K. Esantsi, Gayathri Muthukumar, Kelly C. L. Shaffer, Maxine L. Wang, Angela N. Pogson, Jeff J. Jones, Brett Lomenick, Tsui-Fen Chou, Jonathan S. Weissman, and Rebecca M. Voorhees. Mtch2 is a mitochondrial outer membrane protein insertase. Science, 378:317-322, Oct 2022. URL: https://doi.org/10.1126/science.add1856, doi:10.1126/science.add1856. This article has 162 citations and is from a highest quality peer-reviewed journal.
(gross2024abidmtch2love pages 5-7): Atan Gross. A bid-mtch2 love story: energizing mitochondria until apoptosis do them part? JournalArticle, Jan 2024. URL: https://doi.org/10.26124/bec:2024-0001, doi:10.26124/bec:2024-0001. This article has 0 citations.
(goldman2023mtch2cooperateswith pages 6-8): Andres Goldman, Michael Mullokandov, Yehudit Zaltsman, Limor Regev, Smadar Levin-Zaidman, and Atan Gross. Mtch2 cooperates with mfn2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion. EMBO Reports, 25:45-67, Dec 2023. URL: https://doi.org/10.1038/s44319-023-00009-1, doi:10.1038/s44319-023-00009-1. This article has 30 citations and is from a highest quality peer-reviewed journal.
(goldman2023mtch2cooperateswith pages 1-2): Andres Goldman, Michael Mullokandov, Yehudit Zaltsman, Limor Regev, Smadar Levin-Zaidman, and Atan Gross. Mtch2 cooperates with mfn2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion. EMBO Reports, 25:45-67, Dec 2023. URL: https://doi.org/10.1038/s44319-023-00009-1, doi:10.1038/s44319-023-00009-1. This article has 30 citations and is from a highest quality peer-reviewed journal.
(guo2025mtch2inregulation pages 4-4): Lishu Guo. Mtch2 in regulation of mitochondrial dynamics and metabolism: new insights and perspectives. Organelle, Aug 2025. URL: https://doi.org/10.61747/0ifp.202503004, doi:10.61747/0ifp.202503004. This article has 0 citations.
(peng2024mtch2inmetabolic pages 10-11): Xiaoqing Peng, Yuanyuan Yang, Ruirui Hou, Longbiao Zhang, Can Shen, Xiaoyan Yang, Zhigang Luo, Zongzhi Yin, and Yunxia Cao. Mtch2 in metabolic diseases, neurodegenerative diseases, cancers, embryonic development and reproduction. Drug Design, Development and Therapy, 18:2203-2213, Jun 2024. URL: https://doi.org/10.2147/dddt.s460448, doi:10.2147/dddt.s460448. This article has 20 citations.
(peng2024mtch2inmetabolic pages 6-7): Xiaoqing Peng, Yuanyuan Yang, Ruirui Hou, Longbiao Zhang, Can Shen, Xiaoyan Yang, Zhigang Luo, Zongzhi Yin, and Yunxia Cao. Mtch2 in metabolic diseases, neurodegenerative diseases, cancers, embryonic development and reproduction. Drug Design, Development and Therapy, 18:2203-2213, Jun 2024. URL: https://doi.org/10.2147/dddt.s460448, doi:10.2147/dddt.s460448. This article has 20 citations.
(guna2022mtch2isa pages 4-6): Alina Guna, Taylor A. Stevens, Alison J. Inglis, Joseph M. Replogle, Theodore K. Esantsi, Gayathri Muthukumar, Kelly C. L. Shaffer, Maxine L. Wang, Angela N. Pogson, Jeff J. Jones, Brett Lomenick, Tsui-Fen Chou, Jonathan S. Weissman, and Rebecca M. Voorhees. Mtch2 is a mitochondrial outer membrane protein insertase. Science, 378:317-322, Oct 2022. URL: https://doi.org/10.1126/science.add1856, doi:10.1126/science.add1856. This article has 162 citations and is from a highest quality peer-reviewed journal.
(chourasia2023highenergydemandand pages 1-5): Sabita Chourasia, Christopher Petucci, Hu Wang, Xianlin Han, Ehud Sivan, Alexander Brandis, Tevie Mehlman, Sergey Malitsky, Maxim Itkin, Ron Rotkopf, Limor Regev, Yehudit Zaltsman, and Atan Gross. High-energy demand and nutrient exhaustion in mtch2 knockout cells. bioRxiv, Dec 2023. URL: https://doi.org/10.1101/2023.12.15.571941, doi:10.1101/2023.12.15.571941. This article has 1 citations.
id: Q9Y6C9
gene_symbol: MTCH2
product_type: PROTEIN
status: INITIALIZED
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: Mitochondrial outer membrane protein insertase that mediates insertion
of alpha-helical transmembrane proteins (signal-anchored, tail-anchored, and
multi-pass) into the outer membrane. Identified by Guna et al. 2022 as the
metazoan functional equivalent of the yeast Mim1/Mim2 complex, despite no
sequence homology. Uses a diverged solute carrier fold. Does not insert
beta-barrel proteins (handled by SAM/SAMM50). Also implicated in apoptosis
(tBID receptor), mitochondrial fusion, lipid homeostasis, and stem cell biology,
but the core evolved function is as an outer membrane insertase.
existing_annotations:
- term:
id: GO:0005739
label: mitochondrion
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Too general — MTCH2 specifically localizes to the mitochondrial outer
membrane (PMID:36264797).
action: MARK_AS_OVER_ANNOTATED
reason: Subsumed by mitochondrial outer membrane annotation.
- term:
id: GO:0016020
label: membrane
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Extremely generic. MTCH2 is a multi-pass OM protein.
action: MARK_AS_OVER_ANNOTATED
reason: Subsumed by mitochondrial outer membrane.
- term:
id: GO:0043065
label: positive regulation of apoptotic process
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: MTCH2 acts as tBID receptor at the OM, facilitating BAX/BAK activation.
This is a well-characterized secondary function, but the core evolved function
is as an insertase. Apoptotic role may be secondary to its insertase activity.
action: KEEP_AS_NON_CORE
reason: Secondary function; the insertase role is core.
- term:
id: GO:0005741
label: mitochondrial outer membrane
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Correct. MTCH2 is a multi-pass protein of the mitochondrial outer
membrane. Directly demonstrated (PMID:36264797).
action: ACCEPT
supported_by:
- reference_id: file:human/MTCH2/MTCH2-deep-research-falcon.md
supporting_text: Falcon synthesis supports MTCH2 as an integral mitochondrial
outer membrane protein with carrier-fold-related topology.
- term:
id: GO:0070585
label: protein localization to mitochondrion
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: MTCH2 mediates insertion of proteins into the OM, which could be
considered protein localization. However the more specific insertase terms
are more informative.
action: KEEP_AS_NON_CORE
reason: Generic; the specific insertase annotation is more informative.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
review:
summary: HuRI binary interactome screen. Protein binding is uninformative.
action: REMOVE
reason: Protein binding is uninformative per guidelines.
- term:
id: GO:0010635
label: regulation of mitochondrial fusion
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Mouse MTCH2 KO affects mitochondrial fusion (Bahat et al.). This may
be secondary to insertase function — fusion machinery (MFN1/2) requires OM
insertion. Non-core pleiotropic effect.
action: KEEP_AS_NON_CORE
reason: Likely downstream of insertase function affecting fusion machinery insertion.
- term:
id: GO:0043065
label: positive regulation of apoptotic process
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Ensembl Compara transfer. Redundant with IBA. Non-core function.
action: KEEP_AS_NON_CORE
reason: Secondary function; insertase role is core.
- term:
id: GO:0055088
label: lipid homeostasis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Mouse studies showed MTCH2 role in adipocyte differentiation and lipid
metabolism. Pleiotropic effect, likely downstream of insertase function.
action: KEEP_AS_NON_CORE
reason: Pleiotropic downstream effect.
- term:
id: GO:2000738
label: positive regulation of stem cell differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Mouse studies showed MTCH2 role in ESC naive-to-primed transition and
HSC cycling. Pleiotropic effect.
action: KEEP_AS_NON_CORE
reason: Pleiotropic downstream effect of insertase function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:40105103
review:
summary: Oezdemir et al. 2025 defined TOM interactome, found MTCH2 interaction.
Protein binding uninformative.
action: REMOVE
reason: Protein binding uninformative per guidelines.
- term:
id: GO:0005739
label: mitochondrion
evidence_type: HTP
original_reference_id: PMID:34800366
review:
summary: HTP proteome confirms mitochondrial localization. Too general.
action: MARK_AS_OVER_ANNOTATED
reason: Subsumed by mitochondrial outer membrane annotation.
- term:
id: GO:0005741
label: mitochondrial outer membrane
evidence_type: IDA
original_reference_id: PMID:36264797
review:
summary: Guna et al. 2022 directly demonstrated MTCH2 is a multi-pass protein
of the mitochondrial outer membrane. Core CC annotation from the landmark
insertase paper.
action: ACCEPT
supported_by:
- reference_id: PMID:36264797
supporting_text: MTCH2 is a mitochondrial outer membrane protein insertase.
- reference_id: file:human/MTCH2/MTCH2-deep-research-falcon.md
supporting_text: Falcon synthesis identifies MTCH2 as an integral OMM
insertase for alpha-helical mitochondrial outer membrane substrates.
- term:
id: GO:0032977
label: membrane insertase activity
evidence_type: IDA
original_reference_id: PMID:36264797
review:
summary: Guna et al. 2022 demonstrated MTCH2 is both necessary and sufficient
for insertion of alpha-helical OM proteins using CRISPR screens and
reconstitution assays. This is the core molecular function of MTCH2.
action: ACCEPT
supported_by:
- reference_id: PMID:36264797
supporting_text: 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 α-helical mitochondrial outer membrane proteins.
- reference_id: file:human/MTCH2/MTCH2-deep-research-falcon.md
supporting_text: Falcon synthesis supports membrane insertase activity as
the most strongly supported primary molecular function of MTCH2.
- term:
id: GO:0045040
label: protein insertion into mitochondrial outer membrane
evidence_type: IDA
original_reference_id: PMID:36264797
review:
summary: Guna et al. 2022 showed MTCH2 mediates insertion of signal-anchored,
tail-anchored, and multi-pass alpha-helical proteins into the OM. Core BP.
action: ACCEPT
supported_by:
- reference_id: PMID:36264797
supporting_text: MTCH2’s role also appears to extend to the integration of a
broader class of α-helical proteins into the outer membrane, including
signal anchored and multipass proteins.
- reference_id: file:human/MTCH2/MTCH2-deep-research-falcon.md
supporting_text: Falcon synthesis supports protein insertion into the
mitochondrial outer membrane as the core MTCH2 biological process.
- term:
id: GO:0010635
label: regulation of mitochondrial fusion
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Ortholog-based transfer from mouse. Non-core pleiotropic effect.
action: KEEP_AS_NON_CORE
reason: Downstream of insertase function.
- term:
id: GO:0043065
label: positive regulation of apoptotic process
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Ortholog transfer. Non-core, redundant with IBA and IEA.
action: KEEP_AS_NON_CORE
reason: Secondary function.
- term:
id: GO:0055088
label: lipid homeostasis
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Ortholog transfer. Non-core pleiotropic effect.
action: KEEP_AS_NON_CORE
reason: Pleiotropic downstream effect.
- term:
id: GO:2000738
label: positive regulation of stem cell differentiation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Ortholog transfer. Non-core pleiotropic effect.
action: KEEP_AS_NON_CORE
reason: Pleiotropic downstream effect.
- term:
id: GO:0016020
label: membrane
evidence_type: HDA
original_reference_id: PMID:19946888
review:
summary: NK cell membrane proteomics. Extremely generic.
action: MARK_AS_OVER_ANNOTATED
reason: Subsumed by mitochondrial outer membrane.
- term:
id: GO:0070585
label: protein localization to mitochondrion
evidence_type: IMP
original_reference_id: PMID:23744079
review:
summary: Shamas-Din et al. 2013 studied tBid conformational changes at the OM.
MTCH2 facilitates tBid recruitment to mitochondria, which is part of its
apoptotic function. Non-core.
action: KEEP_AS_NON_CORE
reason: Reflects apoptotic tBid receptor function, not core insertase activity.
- term:
id: GO:0005634
label: nucleus
evidence_type: HDA
original_reference_id: PMID:21630459
review:
summary: Sperm nucleus proteomics. MTCH2 is an outer mitochondrial membrane
protein. Nuclear localization in sperm is likely an artifact of sperm
ultrastructure where mitochondria wrap the midpiece close to the nucleus.
action: REMOVE
reason: Likely artifact. MTCH2 is a mitochondrial outer membrane protein with
no known nuclear function.
core_functions:
- molecular_function:
id: GO:0032977
label: membrane insertase activity
description: >-
MTCH2 is a mitochondrial outer membrane protein insertase that mediates insertion
of alpha-helical transmembrane proteins (signal-anchored, tail-anchored, and
multi-pass) into the outer membrane. Identified as the metazoan functional
equivalent of the yeast Mim1/Mim2 complex via genome-wide CRISPR screens,
despite no sequence homology. Uses a diverged solute carrier fold. Does not
insert beta-barrel proteins (handled by SAM/SAMM50). MTCH1 paralog can also
function as an insertase.
directly_involved_in:
- id: GO:0045040
label: protein insertion into mitochondrial outer membrane
locations:
- id: GO:0005741
label: mitochondrial outer membrane
supported_by:
- reference_id: PMID:36264797
supporting_text: >-
we have demonstrated that MTCH2 is a defining member of a family of membrane
protein insertases that are necessary and sufficient for insertion of TAs into
human mitochondria.
- reference_id: file:human/MTCH2/MTCH2-deep-research-falcon.md
supporting_text: >-
Falcon synthesis supports MTCH2 as a mitochondrial outer membrane insertase
for tail-anchored, signal-anchored, and selected multipass alpha-helical
substrates, with apoptosis, fusion, and lipid phenotypes treated as secondary
or emerging functions.
references:
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
by curator judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to
orthologs using Ensembl Compara
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:19946888
title: Defining the membrane proteome of NK cells.
findings: []
- id: PMID:21630459
title: Proteomic characterization of the human sperm nucleus.
findings: []
- id: PMID:23744079
title: tBid undergoes multiple conformational changes at the membrane required for
Bax activation.
findings: []
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings: []
- id: PMID:34800366
title: Quantitative high-confidence human mitochondrial proteome and its dynamics
in cellular context.
findings: []
- id: PMID:36264797
title: MTCH2 is a mitochondrial outer membrane protein insertase.
findings: []
- id: PMID:40105103
title: Definition of the human mitochondrial TOM interactome reveals TRABD as a
new interacting protein.
findings: []
- id: file:human/MTCH2/MTCH2-deep-research-falcon.md
title: Falcon deep research report for human MTCH2
findings:
- statement: MTCH2 is an integral mitochondrial outer membrane protein whose most
strongly supported primary function is insertion of alpha-helical outer
membrane proteins.
- statement: MTCH2 can facilitate BID/tBID-associated mitochondrial apoptosis,
but this is best treated as non-core relative to the insertase function.
- statement: Recent work links MTCH2 to mitochondrial fusion and lipid metabolism,
including MFN2/LPA-associated fusion plasticity, as secondary or emerging
functional contexts.