Mdm12 (mitochondrial distribution and morphology 12; YOL009C) is the soluble, cytosolic SMP-domain subunit of the ER-mitochondria encounter structure (ERMES). It has no transmembrane segment and is held at ER-mitochondria contacts by its partners: its SMP domain binds the SMP domain of the ER-anchored Mmm1 to form an Mmm1-Mdm12 heterotetramer, and it bridges Mmm1 to the outer membrane SMP-domain subunit Mdm34, giving a zig-zag bridge of SMP domains across the contact. Crystal structures show a hydrophobic phospholipid-binding channel in Mdm12, which binds glycerophospholipids. Free Mdm12 transfers lipids between liposomes only weakly, whereas the Mmm1-Mdm12 complex is an efficient lipid transfer unit, and mutations in the Mdm12 pocket impair phosphatidylserine transport from the ER to mitochondria. Mdm12 is required for assembly of ERMES foci and for the Mmm1-Mdm10 connection. Its loss causes giant spherical mitochondria defective in inheritance, mtDNA nucleoid loss, reduced cardiolipin and an increase in peroxisome number; the mitochondrial defects are rescued by an artificial ER-mitochondria tether. Mdm12 has also been implicated with Mmm1 in a late step of outer membrane beta-barrel protein assembly.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000001 mitochondrion inheritance | IMP PMID:9024686 Mdm12p, a component required for mitochondrial inheritance t... | KEEP AS NON CORE | Summary: Mitochondrion inheritance (IMP): mdm12 cells have giant round mitochondria that are defective for inheritance by daughter buds. Reason: A correctly recorded mutant phenotype, and the historical basis of the MDM name. Mdm12 is not known to perform a step of mitochondrial transport into the bud: the defect is most plausibly secondary to the collapse of the mitochondrial network and loss of ER-mitochondria tethering (the morphology defect of mdm12 cells is restored by an artificial tether, and ERMES-deficiency phenotypes are bypassed by VPS13 alleles; Nguyen et al. 2012 concluded directly that ERMES-mutant inheritance defects are secondary to the morphology defect). Kept, deferring to the experimental record, as non-core. Supporting Evidence: PMID:9024686 possess abnormally large, round mitochondria that are defective for inheritance by daughter buds PMID:22409400 we report that mitochondrial inheritance defects in ERMES mutants are a secondary consequence of mitochondrial morphology defects, arguing against a primary role for ERMES in mitochondrial association with actin and mitochondrial movement PMID:19556461 ChiMERA expression also restored the mitochondrial morphology of mdm12Ξ and mdm34Ξ strains PMID:26370498 The fact that it suppresses ERMES mtDNA defects indicates that these are secondary to the loss of a primary ERMES function. |
| GO:0005515 protein binding | IPI PMID:16093310 Large-scale identification of yeast integral membrane protei... | REMOVE | Summary: Generic protein binding from an interaction study (split-ubiquitin membrane yeast two-hybrid screen). Reason: Generic protein binding (GO:0005515) conveys no functional information. The interaction itself is not disputed: it reflects MDM12's membership of ERMES (and, for Mdm10, of the SAM complex), which is already captured by the part_of ERMES complex / SAM complex annotations and, functionally, by the tether and lipid transfer activity rows. No more informative molecular function can be read from binary interaction data alone, so the row is removed rather than modified. Supporting Evidence: PMID:16093310 by using a modified split-ubiquitin technique |
| GO:0005515 protein binding | IPI PMID:17410204 The morphology proteins Mdm12/Mmm1 function in the major bet... | REMOVE | Summary: Generic protein binding from an interaction study (Mdm12/Mmm1 beta-barrel assembly study). Reason: Generic protein binding (GO:0005515) conveys no functional information. The interaction itself is not disputed: it reflects MDM12's membership of ERMES (and, for Mdm10, of the SAM complex), which is already captured by the part_of ERMES complex / SAM complex annotations and, functionally, by the tether and lipid transfer activity rows. No more informative molecular function can be read from binary interaction data alone, so the row is removed rather than modified. Supporting Evidence: PMID:17410204 Mdm12/Mmm1 function after SAM(core) yet before splitting of the major pathway. |
| GO:0005515 protein binding | IPI PMID:17410204 The morphology proteins Mdm12/Mmm1 function in the major bet... | REMOVE | Summary: Generic protein binding from an interaction study (Mdm12/Mmm1 beta-barrel assembly study). Reason: Generic protein binding (GO:0005515) conveys no functional information. The interaction itself is not disputed: it reflects MDM12's membership of ERMES (and, for Mdm10, of the SAM complex), which is already captured by the part_of ERMES complex / SAM complex annotations and, functionally, by the tether and lipid transfer activity rows. No more informative molecular function can be read from binary interaction data alone, so the row is removed rather than modified. Supporting Evidence: PMID:17410204 Mdm12/Mmm1 function after SAM(core) yet before splitting of the major pathway. |
| GO:0005515 protein binding | IPI PMID:20111053 Mdm10 as a dynamic constituent of the TOB/SAM complex direct... | REMOVE | Summary: Generic protein binding from an interaction study (Mdm10 in TOB/SAM and MMM1 complexes). Reason: Generic protein binding (GO:0005515) conveys no functional information. The interaction itself is not disputed: it reflects MDM12's membership of ERMES (and, for Mdm10, of the SAM complex), which is already captured by the part_of ERMES complex / SAM complex annotations and, functionally, by the tether and lipid transfer activity rows. No more informative molecular function can be read from binary interaction data alone, so the row is removed rather than modified. Supporting Evidence: PMID:20111053 Mdm10 is distributed in the TOB complex for beta-barrel protein assembly and in the MMM1 complex for tethering of the endoplasmic reticulum and mitochondria. |
| GO:0005515 protein binding | IPI PMID:20111053 Mdm10 as a dynamic constituent of the TOB/SAM complex direct... | REMOVE | Summary: Generic protein binding from an interaction study (Mdm10 in TOB/SAM and MMM1 complexes). Reason: Generic protein binding (GO:0005515) conveys no functional information. The interaction itself is not disputed: it reflects MDM12's membership of ERMES (and, for Mdm10, of the SAM complex), which is already captured by the part_of ERMES complex / SAM complex annotations and, functionally, by the tether and lipid transfer activity rows. No more informative molecular function can be read from binary interaction data alone, so the row is removed rather than modified. Supporting Evidence: PMID:20111053 Mdm10 is distributed in the TOB complex for beta-barrel protein assembly and in the MMM1 complex for tethering of the endoplasmic reticulum and mitochondria. |
| GO:0005515 protein binding | IPI PMID:21825164 The conserved GTPase Gem1 regulates endoplasmic reticulum-mi... | REMOVE | Summary: Generic protein binding from an interaction study (purification of ERMES and identification of Gem1). Reason: Generic protein binding (GO:0005515) conveys no functional information. The interaction itself is not disputed: it reflects MDM12's membership of ERMES (and, for Mdm10, of the SAM complex), which is already captured by the part_of ERMES complex / SAM complex annotations and, functionally, by the tether and lipid transfer activity rows. No more informative molecular function can be read from binary interaction data alone, so the row is removed rather than modified. Supporting Evidence: PMID:21825164 Here we purified ERMES complexes and identified the Ca(2+)-binding Miro GTPase Gem1 as an integral component of ERMES. |
| GO:0005634 nucleus | HDA PMID:22842922 Dissecting DNA damage response pathways by analysing protein... | MARK AS OVER ANNOTATED | Summary: Nucleus, from a genome-wide GFP localization screen under DNA replication stress. Reason: No targeted study places Mdm12 in the nucleus; it is a cytosolic ERMES subunit concentrated at ER-mitochondria contacts, and when ERMES is disrupted it partitions to ER or mitochondria, not the nucleus. A perinuclear ER signal (Mdm12 relocalizes to the ER, including the nuclear envelope, in mdm10/mdm34 cells) can be scored as nuclear in high-throughput image classification. Mdm12 is not named in the cached text. Supporting Evidence: PMID:22842922 We use high-throughput microscopic screening of the yeast GFP fusion collection to develop a systems-level view of protein reorganization following drug-induced DNA replication stress. PMID:19556461 Mdm12-GFP, a membrane peripheral protein (fig. S3), relocalized to the ER in the absence of Mdm10 or Mdm34, and the mitochondria in the absence of Mmm1 |
| GO:0005737 cytoplasm | HDA PMID:22842922 Dissecting DNA damage response pathways by analysing protein... | KEEP AS NON CORE | Summary: Cytoplasm, from a genome-wide GFP localization screen. Reason: Correct in the sense that Mdm12 is a soluble protein on the cytosolic face of the ER-mitochondria contact; the informative location is the contact site / ERMES complex. Supporting Evidence: PMID:37366411 Mmm1 is an ER-resident membrane protein, Mdm10 and Mdm34 are mitochondrial outer membrane (MOM) proteins, and Mdm12 is a soluble subunit |
| GO:0005739 mitochondrion | HDA PMID:16823961 Toward the complete yeast mitochondrial proteome: multidimen... | KEEP AS NON CORE | Summary: Mitochondrion, from mitochondrial proteomics. Reason: Mdm12 co-purifies with mitochondria through its association with the outer membrane ERMES subunits; correct but uninformative relative to the outer membrane and ERMES terms. Supporting Evidence: PMID:16823961 A total of 851 different proteins (PROMITO dataset) were identified by use of multidimensional LC-MS/MS PMID:19556461 Mdm12-GFP, a membrane peripheral protein (fig. S3), relocalized to the ER in the absence of Mdm10 or Mdm34, and the mitochondria in the absence of Mmm1 |
| GO:0005741 mitochondrial outer membrane | IDA PMID:9024686 Mdm12p, a component required for mitochondrial inheritance t... | ACCEPT | Summary: Mitochondrial outer membrane (IDA) from immunofluorescence and fractionation (Berger et al. 1997). Reason: Mdm12 is associated with the cytosolic face of the outer membrane via Mdm34/Mdm10. The 1997 paper described it as integral, whereas later work shows it is a peripheral/soluble subunit, but 'located_in mitochondrial outer membrane' is acceptable for a peripheral membrane protein. Supporting Evidence: PMID:9024686 The S. cerevisiae Mdm12p was localized by indirect immunofluorescence microscopy and by subcellular fractionation and immunodetection to the mitochondrial outer membrane PMID:19556461 Mdm12-GFP, a membrane peripheral protein (fig. S3), relocalized to the ER in the absence of Mdm10 or Mdm34, and the mitochondria in the absence of Mmm1 |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Mitochondrial outer membrane, automated. Reason: Consistent with experimental evidence for peripheral outer membrane association. Supporting Evidence: PMID:9024686 The S. cerevisiae Mdm12p was localized by indirect immunofluorescence microscopy and by subcellular fractionation and immunodetection to the mitochondrial outer membrane |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Endoplasmic reticulum membrane, automated. Reason: Mdm12 binds Mmm1 on the cytosolic face of the ER membrane and relocalizes to the ER when Mdm10 or Mdm34 is missing. As a peripheral protein at the contact, it is equally associated with both membranes; the contact-site term is the informative one. Supporting Evidence: PMID:19556461 Mdm12-GFP, a membrane peripheral protein (fig. S3), relocalized to the ER in the absence of Mdm10 or Mdm34, and the mitochondria in the absence of Mmm1 |
| GO:0005886 plasma membrane | HDA PMID:22842922 Dissecting DNA damage response pathways by analysing protein... | MARK AS OVER ANNOTATED | Summary: Plasma membrane, from a genome-wide GFP localization screen. Reason: Not supported by any targeted localization of Mdm12, which is confined to ER-mitochondria contacts. Peripheral (cortical) ER signal and cortical mitochondria can be mis-scored as plasma membrane in automated classification. Mdm12 is not named in the cached text. Supporting Evidence: PMID:22842922 We use high-throughput microscopic screening of the yeast GFP fusion collection to develop a systems-level view of protein reorganization following drug-induced DNA replication stress. PMID:37366411 Mmm1 is an ER-resident membrane protein, Mdm10 and Mdm34 are mitochondrial outer membrane (MOM) proteins, and Mdm12 is a soluble subunit |
| GO:0006869 lipid transport | IEA GO_REF:0000117 | ACCEPT | Summary: Lipid transport, ARBA. Reason: Correct but general; the specific process is phospholipid transfer between ER and mitochondria. Supporting Evidence: PMID:29279306 Therefore, the Mmm1-Mdm12 complex functions as a minimal unit that mediates lipid transfer between membranes. |
| GO:0007005 mitochondrion organization | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Mitochondrion organization (IEA, InterPro) based on the classic mdm/mmm abnormal mitochondrial morphology phenotype of MDM12 mutants. Reason: Loss of any ERMES subunit converts the tubular mitochondrial network into a few giant spherical mitochondria, which is how these genes were discovered. The phenotype is real, but it is largely a downstream consequence of losing ER-mitochondria tethering and lipid supply: an artificial tether restores morphology of mdm12 and mdm34 mutants, and dominant VPS13 alleles suppress ERMES-deficiency phenotypes. The term is broad and correct at the level of necessity, but it is not the core activity, so it is kept as non-core rather than removed. Supporting Evidence: PMID:19556461 mdm12Ξ, mmm1Ξ, mdm10Ξ, and mdm34Ξ strains displayed enlarged and spherical mitochondria as compared with the tubular WT mitochondria PMID:19556461 ChiMERA expression also restored the mitochondrial morphology of mdm12Ξ and mdm34Ξ strains |
| GO:0007005 mitochondrion organization | NAS PMID:21945531 Composition and topology of the endoplasmic reticulum-mitoch... | KEEP AS NON CORE | Summary: Mitochondrion organization (NAS) based on the classic mdm/mmm abnormal mitochondrial morphology phenotype of MDM12 mutants. Reason: Loss of any ERMES subunit converts the tubular mitochondrial network into a few giant spherical mitochondria, which is how these genes were discovered. The phenotype is real, but it is largely a downstream consequence of losing ER-mitochondria tethering and lipid supply: an artificial tether restores morphology of mdm12 and mdm34 mutants, and dominant VPS13 alleles suppress ERMES-deficiency phenotypes. The term is broad and correct at the level of necessity, but it is not the core activity, so it is kept as non-core rather than removed. Supporting Evidence: PMID:21945531 Four ERMES proteins are known in yeast, the ER-anchored protein Mmm1 and three mitochondria-associated proteins, Mdm10, Mdm12 and Mdm34, with functions related to mitochondrial morphology and protein biogenesis. PMID:19556461 ChiMERA expression also restored the mitochondrial morphology of mdm12Ξ and mdm34Ξ strains |
| GO:0007031 peroxisome organization | IMP PMID:30908556 Contribution of ERMES subunits to mature peroxisome abundanc... | KEEP AS NON CORE | Summary: Peroxisome organization (IMP): mdm12 deletion increases the number of mature peroxisomes. Reason: Reproducible phenotype that requires Mmm1 and Pex11 and appears to result from an altered Mmm1/Mdm12 stoichiometry rather than from Mdm12 performing a step of peroxisome biogenesis. Genuine but non-core. Supporting Evidence: PMID:30908556 First, we confirmed previous studies from other groups showing that absence of Mdm10 or Mdm12 leads to an increased number of mature peroxisomes. PMID:30908556 Our results showed that deregulation of peroxisome abundance can only be observed when the Mmm1/Mdm12 stoichiometry is changed either because the Mdm12 protein is absent and the Mmm1/Mdm12 complex cannot be formed, or because Mmm1 is overproduced and free ER-resident Mmm1 protein may accumulate. |
| GO:0008289 lipid binding | IEA GO_REF:0000002 | ACCEPT | Summary: Lipid binding, InterPro (SMP domain). Reason: Experimentally confirmed: Mdm12 crystal structures contain bound phospholipid in a hydrophobic channel. Phospholipid binding would be more specific. Supporting Evidence: PMID:27821511 Biochemical experiments reveal a phospholipidβbinding site located along a hydrophobic channel of the Mdm12 structure PMID:29279306 found that both Mdm12 proteins possess a hydrophobic pocket for phospholipid binding |
| GO:0012505 endomembrane system | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Endomembrane system (IEA, ARBA rule). Reason: Mdm12 is a soluble protein bound to Mmm1 on the cytosolic face of the ER at contacts. In GO, ERMES complex has endomembrane system among its ancestors (via the ER-anchored subunit), so this broad automated term is ontology-consistent, but it is uninformative relative to the ERMES complex and contact-site annotations. Supporting Evidence: PMID:37366411 Mmm1 is an ER-resident membrane protein, Mdm10 and Mdm34 are mitochondrial outer membrane (MOM) proteins, and Mdm12 is a soluble subunit |
| GO:0015914 phospholipid transport | IBA GO_REF:0000033 | ACCEPT | Summary: Phospholipid transport (IBA) for MDM12. Reason: ERMES mediates non-vesicular phospholipid transfer from the ER to mitochondria: ERMES mutants show a two- to fivefold reduction in PS-to-PC conversion, isolated membranes lacking Mmm1, Mdm12 or Mdm34 are defective in PS transport from ER to mitochondria, the purified Mmm1-Mdm12 complex transfers phospholipids between liposomes, and in vivo mass-tagging (METALIC) shows ERMES transport activity in living cells. An earlier in vivo radiolabelling study (Nguyen et al. 2012, PMID:22409400) found PS-to-PE conversion unaffected in ERMES mutants; this is now generally explained by redundant routes (Vps13-Mcp1 at vacuole-mitochondria contacts) rather than by absence of ERMES transfer activity. Sound node placement within the MDM12 family. Supporting Evidence: PMID:29279306 In contrast, Mdm12 in a complex with Mmm1 mediated efficient lipid transfer between liposomes. PMID:35654841 we show that the ERMES and Vps13-Mcp1 complexes have transport activity in vivo |
| GO:0015914 phospholipid transport | IGI PMID:19556461 An ER-mitochondria tethering complex revealed by a synthetic... | ACCEPT | Summary: Phospholipid transport (IGI) for MDM12. Reason: ERMES mediates non-vesicular phospholipid transfer from the ER to mitochondria: ERMES mutants show a two- to fivefold reduction in PS-to-PC conversion, isolated membranes lacking Mmm1, Mdm12 or Mdm34 are defective in PS transport from ER to mitochondria, the purified Mmm1-Mdm12 complex transfers phospholipids between liposomes, and in vivo mass-tagging (METALIC) shows ERMES transport activity in living cells. An earlier in vivo radiolabelling study (Nguyen et al. 2012, PMID:22409400) found PS-to-PE conversion unaffected in ERMES mutants; this is now generally explained by redundant routes (Vps13-Mcp1 at vacuole-mitochondria contacts) rather than by absence of ERMES transfer activity. Supporting Evidence: PMID:19556461 Mutants of ERMES showed a two- to fivefold reduction in PS-to-PC conversion rate PMID:19556461 Thus, ERMES-mediated ER-mitochondria connections are necessary for efficient inter-organellar phospholipid exchange. |
| GO:0015914 phospholipid transport | IMP PMID:29279306 Structure-function insights into direct lipid transfer betwe... | ACCEPT | Summary: Phospholipid transport (IMP, acts_upstream_of_or_within) for MDM12. Reason: ERMES mediates non-vesicular phospholipid transfer from the ER to mitochondria: ERMES mutants show a two- to fivefold reduction in PS-to-PC conversion, isolated membranes lacking Mmm1, Mdm12 or Mdm34 are defective in PS transport from ER to mitochondria, the purified Mmm1-Mdm12 complex transfers phospholipids between liposomes, and in vivo mass-tagging (METALIC) shows ERMES transport activity in living cells. An earlier in vivo radiolabelling study (Nguyen et al. 2012, PMID:22409400) found PS-to-PE conversion unaffected in ERMES mutants; this is now generally explained by redundant routes (Vps13-Mcp1 at vacuole-mitochondria contacts) rather than by absence of ERMES transfer activity. Mdm12 pocket mutations lower the transfer activity of the Mmm1-Mdm12 complex; Mdm12 does part of the work. Supporting Evidence: PMID:29279306 Mutations in Mmm1 or Mdm12 impaired the lipid transfer activities of the Mdm12-Mmm1 complex and furthermore caused defective phosphatidylserine transport from the ER to mitochondrial membranes via ERMES in vitro. PMID:29279306 This indicates that the lipid transfer activity of the Mmm1sβMdm12 complex between membranes arises from the cooperation of Mmm1s and Mdm12. |
| GO:0015917 aminophospholipid transport | IMP PMID:27469264 A phospholipid transfer function of ER-mitochondria encounte... | ACCEPT | Summary: Aminophospholipid (phosphatidylserine) transport from ER to mitochondria impaired in mdm12 membranes. Reason: Direct mutant evidence for a lipid-transferring subunit; direction is ER-to-mitochondria (PE export was ERMES-independent in the same assay). Supporting Evidence: PMID:27469264 In the absence of Mmm1, Mdm12 or Mdm34 the PS transport from the ER to mitochondria was significantly impaired PMID:27469264 Taken together, we conclude that ERMES plays a critical role in facilitating the PS transport from the ER to mitochondria. PMID:27469264 It is thus likely that the PE transport is primarily mediated by uncharacterized factors other than ERMES. |
| GO:0032865 ERMES complex | IBA GO_REF:0000033 | ACCEPT | Summary: MDM12 is a core subunit of the ER-mitochondria encounter structure (ERMES); IBA evidence. Reason: ERMES membership of MDM12 is among the best-established facts about this protein: the four core subunits (Mmm1, Mdm10, Mdm12, Mdm34) co-purify, co-immunoprecipitate, co-localize in a few discrete foci at ER-mitochondria contacts and are mutually required for focus formation. Gem1 is a fifth, regulatory subunit. This is the central cellular component for the gene and is used as in_complex in core_functions. Supporting Evidence: PMID:19556461 We identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a molecular tether between ER and mitochondria. PMID:21945531 Four ERMES proteins are known in yeast, the ER-anchored protein Mmm1 and three mitochondria-associated proteins, Mdm10, Mdm12 and Mdm34, with functions related to mitochondrial morphology and protein biogenesis. |
| GO:0032865 ERMES complex | IEA GO_REF:0000120 | ACCEPT | Summary: MDM12 is a core subunit of the ER-mitochondria encounter structure (ERMES); IEA evidence. Reason: ERMES membership of MDM12 is among the best-established facts about this protein: the four core subunits (Mmm1, Mdm10, Mdm12, Mdm34) co-purify, co-immunoprecipitate, co-localize in a few discrete foci at ER-mitochondria contacts and are mutually required for focus formation. Gem1 is a fifth, regulatory subunit. This is the central cellular component for the gene and is used as in_complex in core_functions. Supporting Evidence: PMID:19556461 We identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a molecular tether between ER and mitochondria. PMID:21945531 Four ERMES proteins are known in yeast, the ER-anchored protein Mmm1 and three mitochondria-associated proteins, Mdm10, Mdm12 and Mdm34, with functions related to mitochondrial morphology and protein biogenesis. |
| GO:0032865 ERMES complex | IPI PMID:13679517 A protein complex containing Mdm10p, Mdm12p, and Mmm1p links... | ACCEPT | Summary: MDM12 is a core subunit of the ER-mitochondria encounter structure (ERMES); IPI evidence. Reason: ERMES membership of MDM12 is among the best-established facts about this protein: the four core subunits (Mmm1, Mdm10, Mdm12, Mdm34) co-purify, co-immunoprecipitate, co-localize in a few discrete foci at ER-mitochondria contacts and are mutually required for focus formation. Gem1 is a fifth, regulatory subunit. This is the central cellular component for the gene and is used as in_complex in core_functions. Supporting Evidence: PMID:19556461 We identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a molecular tether between ER and mitochondria. PMID:21945531 Four ERMES proteins are known in yeast, the ER-anchored protein Mmm1 and three mitochondria-associated proteins, Mdm10, Mdm12 and Mdm34, with functions related to mitochondrial morphology and protein biogenesis. |
| GO:0032865 ERMES complex | IPI PMID:13679517 A protein complex containing Mdm10p, Mdm12p, and Mmm1p links... | ACCEPT | Summary: MDM12 is a core subunit of the ER-mitochondria encounter structure (ERMES); IPI evidence. Reason: ERMES membership of MDM12 is among the best-established facts about this protein: the four core subunits (Mmm1, Mdm10, Mdm12, Mdm34) co-purify, co-immunoprecipitate, co-localize in a few discrete foci at ER-mitochondria contacts and are mutually required for focus formation. Gem1 is a fifth, regulatory subunit. This is the central cellular component for the gene and is used as in_complex in core_functions. Supporting Evidence: PMID:19556461 We identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a molecular tether between ER and mitochondria. PMID:21945531 Four ERMES proteins are known in yeast, the ER-anchored protein Mmm1 and three mitochondria-associated proteins, Mdm10, Mdm12 and Mdm34, with functions related to mitochondrial morphology and protein biogenesis. |
| GO:0032865 ERMES complex | IPI PMID:17410204 The morphology proteins Mdm12/Mmm1 function in the major bet... | ACCEPT | Summary: MDM12 is a core subunit of the ER-mitochondria encounter structure (ERMES); IPI evidence. Reason: ERMES membership of MDM12 is among the best-established facts about this protein: the four core subunits (Mmm1, Mdm10, Mdm12, Mdm34) co-purify, co-immunoprecipitate, co-localize in a few discrete foci at ER-mitochondria contacts and are mutually required for focus formation. Gem1 is a fifth, regulatory subunit. This is the central cellular component for the gene and is used as in_complex in core_functions. Supporting Evidence: PMID:19556461 We identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a molecular tether between ER and mitochondria. PMID:21945531 Four ERMES proteins are known in yeast, the ER-anchored protein Mmm1 and three mitochondria-associated proteins, Mdm10, Mdm12 and Mdm34, with functions related to mitochondrial morphology and protein biogenesis. |
| GO:0032865 ERMES complex | IPI PMID:17410204 The morphology proteins Mdm12/Mmm1 function in the major bet... | ACCEPT | Summary: MDM12 is a core subunit of the ER-mitochondria encounter structure (ERMES); IPI evidence. Reason: ERMES membership of MDM12 is among the best-established facts about this protein: the four core subunits (Mmm1, Mdm10, Mdm12, Mdm34) co-purify, co-immunoprecipitate, co-localize in a few discrete foci at ER-mitochondria contacts and are mutually required for focus formation. Gem1 is a fifth, regulatory subunit. This is the central cellular component for the gene and is used as in_complex in core_functions. Supporting Evidence: PMID:19556461 We identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a molecular tether between ER and mitochondria. PMID:21945531 Four ERMES proteins are known in yeast, the ER-anchored protein Mmm1 and three mitochondria-associated proteins, Mdm10, Mdm12 and Mdm34, with functions related to mitochondrial morphology and protein biogenesis. |
| GO:0032865 ERMES complex | IPI PMID:17410204 The morphology proteins Mdm12/Mmm1 function in the major bet... | ACCEPT | Summary: MDM12 is a core subunit of the ER-mitochondria encounter structure (ERMES); IPI evidence. Reason: ERMES membership of MDM12 is among the best-established facts about this protein: the four core subunits (Mmm1, Mdm10, Mdm12, Mdm34) co-purify, co-immunoprecipitate, co-localize in a few discrete foci at ER-mitochondria contacts and are mutually required for focus formation. Gem1 is a fifth, regulatory subunit. This is the central cellular component for the gene and is used as in_complex in core_functions. Supporting Evidence: PMID:19556461 We identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a molecular tether between ER and mitochondria. PMID:21945531 Four ERMES proteins are known in yeast, the ER-anchored protein Mmm1 and three mitochondria-associated proteins, Mdm10, Mdm12 and Mdm34, with functions related to mitochondrial morphology and protein biogenesis. |
| GO:0032865 ERMES complex | IPI PMID:17410204 The morphology proteins Mdm12/Mmm1 function in the major bet... | ACCEPT | Summary: MDM12 is a core subunit of the ER-mitochondria encounter structure (ERMES); IPI evidence. Reason: ERMES membership of MDM12 is among the best-established facts about this protein: the four core subunits (Mmm1, Mdm10, Mdm12, Mdm34) co-purify, co-immunoprecipitate, co-localize in a few discrete foci at ER-mitochondria contacts and are mutually required for focus formation. Gem1 is a fifth, regulatory subunit. This is the central cellular component for the gene and is used as in_complex in core_functions. Supporting Evidence: PMID:19556461 We identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a molecular tether between ER and mitochondria. PMID:21945531 Four ERMES proteins are known in yeast, the ER-anchored protein Mmm1 and three mitochondria-associated proteins, Mdm10, Mdm12 and Mdm34, with functions related to mitochondrial morphology and protein biogenesis. |
| GO:0032865 ERMES complex | IPI PMID:21945531 Composition and topology of the endoplasmic reticulum-mitoch... | ACCEPT | Summary: MDM12 is a core subunit of the ER-mitochondria encounter structure (ERMES); IPI evidence. Reason: ERMES membership of MDM12 is among the best-established facts about this protein: the four core subunits (Mmm1, Mdm10, Mdm12, Mdm34) co-purify, co-immunoprecipitate, co-localize in a few discrete foci at ER-mitochondria contacts and are mutually required for focus formation. Gem1 is a fifth, regulatory subunit. This is the central cellular component for the gene and is used as in_complex in core_functions. Supporting Evidence: PMID:19556461 We identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a molecular tether between ER and mitochondria. PMID:21945531 Four ERMES proteins are known in yeast, the ER-anchored protein Mmm1 and three mitochondria-associated proteins, Mdm10, Mdm12 and Mdm34, with functions related to mitochondrial morphology and protein biogenesis. |
| GO:0044233 mitochondria-associated endoplasmic reticulum membrane contact site | IDA PMID:37366411 Complementation Assay Using Fusion of Split-GFP and TurboID ... | ACCEPT | Summary: Proximity biotinylation (CsFiND split-GFP/TurboID) at ER-mitochondria contacts labelled MDM12. Reason: ERMES is the defining tether of yeast ER-mitochondria contact sites and MDM12 acts there. The CsFiND reporter specifically biotinylated Mmm1, Mdm12 and Mdm34 (Mdm10 was not detected). The is_active_in qualifier is appropriate; this is the core location for the tethering and lipid-transfer function. Supporting Evidence: PMID:37366411 showed CsFiND specifically biotinylated three of the four ERMES core subunits (Mmm1, Mdm12, and Mdm34) |
| GO:0045040 protein insertion into mitochondrial outer membrane | IEA GO_REF:0000104 | KEEP AS NON CORE | Summary: Protein insertion into mitochondrial outer membrane, UniRule. Reason: Derived from mutant (necessity) evidence that Mdm12/Mmm1 act after SAM(core) in beta-barrel assembly. Mdm12 is not known to perform an insertion step, and indirect effects via outer membrane lipid composition are plausible; kept as non-core. Supporting Evidence: PMID:17410204 Mdm12/Mmm1 function after SAM(core) yet before splitting of the major pathway. |
| GO:0055091 phospholipid homeostasis | NAS PMID:21945531 Composition and topology of the endoplasmic reticulum-mitoch... | KEEP AS NON CORE | Summary: Phospholipid homeostasis (NAS) from the ERMES composition/topology study. Reason: ERMES mutants show reduced cardiolipin and slowed PS-to-PC conversion; these are consequences of impaired ER-to-mitochondria phospholipid transfer, which MDM12 executes as part of ERMES. The homeostasis term is a reasonable but indirect description of that role; the direct process is captured by phospholipid transport / intermembrane lipid transfer. Supporting Evidence: PMID:21945531 ERMES represents a platform that integrates components with functions in formation of ER-mitochondria junctions, maintenance of mitochondrial morphology, protein biogenesis and calcium binding PMID:19556461 A reduced rate of lipid exchange in turn slows down amino-glycerophospholipid turnover, which results in impaired CL synthesis |
| GO:0070096 mitochondrial outer membrane translocase complex assembly | IMP PMID:17410204 The morphology proteins Mdm12/Mmm1 function in the major bet... | KEEP AS NON CORE | Summary: Mitochondrial outer membrane translocase complex assembly (IMP), Meisinger et al. 2007. Reason: Tom40 assembly is impaired in mdm12 mitochondria, but the evidence is necessity; a secondary effect of altered membrane lipids is not excluded, and the SAM-associated ERMES subunit acting directly in TOM assembly is Mdm10. The abstract-only cache does not allow the data to be re-examined. Supporting Evidence: PMID:17410204 Mdm12/Mmm1 function after SAM(core) yet before splitting of the major pathway. PMID:17410204 Mdm12/Mmm1 have been known for their role in maintenance of mitochondrial morphology but we reveal assembly of beta-barrel proteins as their primary function. |
| GO:0098799 outer mitochondrial membrane protein complex | NAS PMID:21945531 Composition and topology of the endoplasmic reticulum-mitoch... | ACCEPT | Summary: Outer mitochondrial membrane protein complex (NAS), a general parent of ERMES complex. Reason: In GO, ERMES complex (GO:0032865) is a descendant of outer mitochondrial membrane protein complex (GO:0098799) (ancestor chain verified in QuickGO), so this NAS row is a correct but less specific restatement of MDM12's ERMES membership. Redundant, not wrong. Supporting Evidence: PMID:21945531 Four ERMES proteins are known in yeast, the ER-anchored protein Mmm1 and three mitochondria-associated proteins, Mdm10, Mdm12 and Mdm34, with functions related to mitochondrial morphology and protein biogenesis. |
| GO:0120009 intermembrane lipid transfer | IEA GO_REF:0000108 | ACCEPT | Summary: Intermembrane lipid transfer, GO logical inference from lipid transfer activity. Reason: The best process term for Mdm12's role in the Mmm1-Mdm12 transfer unit. Supporting Evidence: PMID:29279306 Therefore, the Mmm1-Mdm12 complex functions as a minimal unit that mediates lipid transfer between membranes. PMID:35654841 we show that the ERMES and Vps13-Mcp1 complexes have transport activity in vivo |
| GO:0120013 lipid transfer activity | IDA PMID:29279306 Structure-function insights into direct lipid transfer betwe... | ACCEPT | Summary: Lipid transfer activity (IDA) from liposome transfer assays (Kawano et al. 2018). Reason: Two rows from this paper: contributes_to (efficient transfer by the Mmm1-Mdm12 complex) and enables (weak but measurable transfer by free Mdm12). Both are supported; the contributes_to reading reflects the physiologically relevant activity and is used in core_functions with the more specific phospholipid transfer activity (GO:0120014). Supporting Evidence: PMID:29279306 In contrast, Mdm12 in a complex with Mmm1 mediated efficient lipid transfer between liposomes. PMID:29279306 This indicates that the lipid transfer activity of the Mmm1sβMdm12 complex between membranes arises from the cooperation of Mmm1s and Mdm12. PMID:29279306 However, when tested in vitro, purified free KlMdm12 alone or Mmm1s as a purified fusion protein (MBP-HMmm1s) is capable of extracting phospholipid from donor liposomes and transferring it to acceptor liposomes, but this lipid transfer activity is very low. |
| GO:0120013 lipid transfer activity | IDA PMID:29279306 Structure-function insights into direct lipid transfer betwe... | ACCEPT | Summary: Lipid transfer activity (IDA) from liposome transfer assays (Kawano et al. 2018). Reason: Two rows from this paper: contributes_to (efficient transfer by the Mmm1-Mdm12 complex) and enables (weak but measurable transfer by free Mdm12). Both are supported; the contributes_to reading reflects the physiologically relevant activity and is used in core_functions with the more specific phospholipid transfer activity (GO:0120014). Supporting Evidence: PMID:29279306 In contrast, Mdm12 in a complex with Mmm1 mediated efficient lipid transfer between liposomes. PMID:29279306 This indicates that the lipid transfer activity of the Mmm1sβMdm12 complex between membranes arises from the cooperation of Mmm1s and Mdm12. PMID:29279306 However, when tested in vitro, purified free KlMdm12 alone or Mmm1s as a purified fusion protein (MBP-HMmm1s) is capable of extracting phospholipid from donor liposomes and transferring it to acceptor liposomes, but this lipid transfer activity is very low. |
| GO:0140474 mitochondrion-endoplasmic reticulum membrane tether activity | IDA PMID:19556461 An ER-mitochondria tethering complex revealed by a synthetic... | ACCEPT | Summary: Mitochondrion-ER membrane tether activity for MDM12, from the synthetic-tether (ChiMERA) complementation screen that defined ERMES. Reason: Kornmann et al. 2009 showed that the Mmm1/Mdm10/Mdm12/Mdm34 complex physically links the ER and the mitochondrial outer membrane and that its loss is partly bypassed by an artificial ER-mitochondria tether. Mdm12 is the soluble SMP-domain link that bridges Mmm1 to Mdm34; mdm12 was the mutant recovered in the ChiMERA screen. The MF term describes the activity of the assembled bridge, and each subunit contributes a physically necessary part of it (ER anchor, OM anchor, or the SMP-domain bridge), so the annotation is accepted for every core subunit. GO:1990456 (the former BP for this tethering) was obsoleted in favour of this MF term (verified in QuickGO). Supporting Evidence: PMID:19556461 Thus, one core molecular function of the Mmm1/Mdm10/Mdm12/Mdm34 complex is to connect ER and mitochondria, which can be bypassed by expressing a synthetic tether. PMID:19556461 ERMES consists of the ER-resident membrane protein Mmm1 and the OMM-resident Ξ²-barrel protein Mdm10 |
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Download this section (compressed HTML)Q: Should the nucleus and plasma membrane HDA rows from the replication-stress GFP screen be retired? No targeted study supports either location for Mdm12.
Suggested experts: SGD curators
Q: Does Mdm12 act as a shuttle between Mmm1 and Mdm34 or as a segment of a continuous lipid conduit, and is its lipid-transfer function separable from its bridging role (Covill-Cooke et al. 2026 suggest Mdm12 and Mdm34 may be dispensable for transfer when Mmm1 is artificially tethered)?
Suggested experts: Kornmann lab, Kukulski lab, Egea lab
Q: ERMES is inferred to have been present in the last opisthokont common ancestor and lost in the human lineage (Chen et al. 2026, PMID:42822426), with VPS13-family bridge proteins and other contact-site machinery likely covering ER-mitochondria lipid supply in animals. Which human proteins, if any, should receive the ERMES-equivalent function annotations, and should ERMES complex membership be explicitly excluded for human genes in phylogenetic propagation?
Suggested experts: PAINT curators, Kornmann lab
Experiment: Measure METALIC lipid flux in mdm12 pocket mutants (L10S, V125/V214 substitutions) expressed at endogenous levels, compared with an mdm12 deletion rescued by ChiMERA.
Hypothesis: Mdm12's hydrophobic channel is required for ER-to-mitochondria phospholipid flux in vivo.
Type: lipidomics
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Download this section (compressed HTML)Mitochondrial outer membrane protein, ERMES complex subunit; required for transmission of mitochondria to daughter cells; required for mitophagy; may influence import and assembly of outer membrane beta-barrel proteins; localizes to mitochondriaβER contact sites; ERMES complex is often co-localized with peroxisomes and with concentrated areas of pyruvate dehydrogenase
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