Mdm34 (mitochondrial distribution and morphology 34; also Mmm2; YGL219C) is the mitochondrial outer membrane SMP-domain subunit of the ER-mitochondria encounter structure (ERMES). It lacks alpha-helical transmembrane segments and associates with the outer membrane, where it partners with the beta-barrel subunit Mdm10; its SMP domain contacts the SMP domain of Mdm12, which in turn binds the ER-anchored Mmm1, forming a bridge of three SMP domains across ER-mitochondria contacts. Mdm34 is required for ERMES assembly into contact-site foci and for the Mmm1-Mdm10 connection, and a disordered loop of Mdm34 binds the Miro GTPase Gem1, recruiting this regulatory subunit to ERMES. Loss of Mdm34 slows phosphatidylserine transport from the ER to mitochondria, reduces cardiolipin, collapses the mitochondrial network into giant spheres and causes mtDNA nucleoid loss; the morphology defect is rescued by an artificial ER-mitochondria tether. Mdm34 is predicted, by homology to Mmm1 and Mdm12 and from the in situ ERMES model, to bind lipids and act as the outer-membrane end of the lipid transfer path, but lipid binding or transfer by Mdm34 itself has not been demonstrated. Mdm34 is a ubiquitinated substrate of mitochondria-associated degradation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | HDA PMID:14562095 Global analysis of protein localization in budding yeast. | KEEP AS NON CORE | Summary: Cytoplasm, from the genome-wide C-terminal GFP localization library. Reason: Mdm34 faces the cytosol on the outer membrane at ERMES foci, and a cytosolic call from a punctate mitochondrial-surface signal is understandable; the informative location is the outer membrane / ERMES contact site. Mdm34 is not named in the cached abstract. Supporting Evidence: PMID:14562095 We classify these proteins, representing 75% of the yeast proteome, into 22 distinct subcellular localization categories PMID:19556461 As expected from its assignment as an OMM protein, Mdm34-GFP relocalized uniformly to mitochondria in the absence of Mdm10, Mdm12, and Mmm1 |
| GO:0005739 mitochondrion | HDA PMID:16823961 Toward the complete yeast mitochondrial proteome: multidimen... | ACCEPT | Summary: Mitochondrion, from mitochondrial proteomics. Reason: Correct; Mdm34 is a mitochondrial outer membrane protein. Supporting Evidence: PMID:16823961 A total of 851 different proteins (PROMITO dataset) were identified by use of multidimensional LC-MS/MS PMID:19556461 As expected from its assignment as an OMM protein, Mdm34-GFP relocalized uniformly to mitochondria in the absence of Mdm10, Mdm12, and Mmm1 |
| GO:0005739 mitochondrion | IDA PMID:27044889 Doa1 targets ubiquitinated substrates for mitochondria-assoc... | ACCEPT | Summary: Mitochondrion (IDA) from fractionation and imaging of Mdm34 in the mitochondria-associated degradation study. Reason: Mdm34-HA fractionates with mitochondria and Mdm34-GFP forms mitochondrial foci; Mdm34 is a substrate of the outer membrane MAD pathway. Correct, though less specific than outer membrane. Supporting Evidence: PMID:27044889 Subcellular fractionation of the MDM34-HA, MDM34-HA doa1Ξ, and mdm34ΞPY-HA strains were analyzed as in D. PMID:27044889 Mitochondria-associated degradation (MAD) mediated by the Cdc48 complex and proteasome degrades ubiquitinated mitochondrial outer-membrane proteins. |
| GO:0005741 mitochondrial outer membrane | EXP PMID:19556461 An ER-mitochondria tethering complex revealed by a synthetic... | ACCEPT | Summary: Mitochondrial outer membrane (EXP), Kornmann et al. 2009. Reason: Mdm34-GFP relocalizes uniformly to mitochondria when the other ERMES subunits are absent, consistent with outer membrane residence. Core location. Supporting Evidence: PMID:19556461 As expected from its assignment as an OMM protein, Mdm34-GFP relocalized uniformly to mitochondria in the absence of Mdm10, Mdm12, and Mmm1 |
| GO:0005741 mitochondrial outer membrane | HDA PMID:16407407 Proteomic analysis of the yeast mitochondrial outer membrane... | ACCEPT | Summary: Mitochondrial outer membrane, outer-membrane proteomics. Reason: Consistent with direct evidence. Supporting Evidence: PMID:16407407 the mitochondrial outer membrane not only contains resident proteins but also accumulates a conserved subclass of preproteins destined for internal mitochondrial compartments PMID:19556461 As expected from its assignment as an OMM protein, Mdm34-GFP relocalized uniformly to mitochondria in the absence of Mdm10, Mdm12, and Mmm1 |
| GO:0005741 mitochondrial outer membrane | IDA PMID:14981098 Mmm2p, a mitochondrial outer membrane protein required for y... | ACCEPT | Summary: Mitochondrial outer membrane (IDA), original Mmm2/Mdm34 characterization (Youngman et al. 2004). Reason: Direct fractionation evidence; core location. Supporting Evidence: PMID:14981098 Mmm2p is located in the outer membrane. |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Mitochondrial outer membrane, automated. Reason: Agrees with direct evidence. Supporting Evidence: PMID:14981098 Mmm2p is located in the outer membrane. |
| GO:0006869 lipid transport | IEA GO_REF:0000117 | ACCEPT | Summary: Lipid transport, ARBA. Reason: Correct but general; Mdm34 is required for ERMES-mediated phospholipid transport from ER to mitochondria. Supporting Evidence: PMID:27469264 In the absence of Mmm1, Mdm12 or Mdm34 the PS transport from the ER to mitochondria was significantly impaired |
| GO:0007005 mitochondrion organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Mitochondrion organization (IBA) based on the classic mdm/mmm abnormal mitochondrial morphology phenotype of MDM34 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 | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Mitochondrion organization (IEA, InterPro) based on the classic mdm/mmm abnormal mitochondrial morphology phenotype of MDM34 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 | IMP PMID:11907266 Genetic basis of mitochondrial function and morphology in Sa... | KEEP AS NON CORE | Summary: Mitochondrion organization (IMP, genome-wide deletion screen) based on the classic mdm/mmm abnormal mitochondrial morphology phenotype of MDM34 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:11907266 We pursued a genomic approach to define the complements of genes required for respiratory growth and inheritance of mitochondria with normal morphology in yeast. 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 MDM34 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:0008289 lipid binding | IEA GO_REF:0000002 | ACCEPT | Summary: Lipid binding, InterPro (SMP-LTD domain). Reason: Reasonable domain-based inference: Mdm34 contains an SMP domain, the SMP domains of Mmm1 and Mdm12 bind phospholipids, and the in situ ERMES model places lipids in the Mdm34 cavity. Lipid binding by Mdm34 has not been directly demonstrated, so this is not used as a core function, but nothing argues against it. Supporting Evidence: PMID:29279306 Mdm34 also contains an SMP domain and may thus be another possible lipid-binding component on the mitochondrial surface like Mmm1 in the ER membrane. PMID:37165187 Our molecular model of ERMES reveals a pathway for lipids. |
| GO:0012505 endomembrane system | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Endomembrane system (IEA, ARBA rule). Reason: Mdm34 is an outer mitochondrial membrane protein and is not itself in the endomembrane system. 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 MDM34. 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 MDM34 family. Supporting Evidence: PMID:27469264 In the absence of Mmm1, Mdm12 or Mdm34 the PS transport from the ER to mitochondria was significantly impaired 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 MDM34. 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. Mdm34 is the outer-membrane SMP subunit of the bridge, so it at least provides structure the transfer depends on; whether it transfers lipids itself is open. 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:0032865 ERMES complex | IBA GO_REF:0000033 | ACCEPT | Summary: MDM34 is a core subunit of the ER-mitochondria encounter structure (ERMES); IBA evidence. Reason: ERMES membership of MDM34 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: MDM34 is a core subunit of the ER-mitochondria encounter structure (ERMES); IEA evidence. Reason: ERMES membership of MDM34 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: MDM34 is a core subunit of the ER-mitochondria encounter structure (ERMES); IPI evidence. Reason: ERMES membership of MDM34 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: MDM34 is a core subunit of the ER-mitochondria encounter structure (ERMES); IPI evidence. Reason: ERMES membership of MDM34 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 MDM34. Reason: ERMES is the defining tether of yeast ER-mitochondria contact sites and MDM34 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: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 MDM34 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: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 MDM34'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: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 MDM34, 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. Mdm34 is the outer-membrane SMP subunit that connects Mdm12 to the mitochondrial side and is required for the Mmm1-Mdm10 interaction; mdm34 defects are efficiently bypassed by the artificial tether. 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 |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: Does the Mdm34 SMP domain bind and transfer phospholipids itself? No purified-protein lipid binding or transfer assay exists for Mdm34; the evidence is homology and the in situ ERMES model.
Suggested experts: Egea lab, Kukulski lab, Endo lab
Q: Is Gem1 recruitment through the Mdm34 L248 loop required for ERMES lipid transfer, or only for regulating ERMES focus number and size?
Suggested experts: Kornmann 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: Express and purify the Mdm34 SMP domain (alone and with Mdm12), determine co-purifying lipids by lipidomics and test liposome transfer, followed by pocket-lining mutants in vivo with METALIC.
Hypothesis: The Mdm34 SMP domain binds glycerophospholipids.
Type: biochemical
Loading supporting contentβ¦
Download this section (compressed HTML)Mitochondrial component of the ERMES complex; links the ER to mitochondria and may promote inter-organellar calcium and phospholipid exchange as well as coordinating mitochondrial DNA replication and growth; required for mitophagy; ERMES complex is often co-localized with peroxisomes and with concentrated areas of pyruvate dehydrogenase
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)