Mitofusin 2 (MFN2) is a dynamin-superfamily GTPase anchored in the mitochondrial outer membrane by a hairpin transmembrane segment, with its N-terminal GTPase domain and helical bundle domains facing the cytosol. Together with its paralog MFN1, MFN2 forms homo- and hetero-oligomeric complexes in trans between apposed mitochondria; nucleotide-dependent dimerization of the GTPase domains tethers the membranes and GTP hydrolysis drives outer-membrane fusion, which is coordinated with OPA1-mediated inner-membrane fusion. MFN2 also concentrates at ER-mitochondria contacts and has been proposed to tether the two organelles, connects mitochondria to the Miro/TRAK transport machinery, and in damaged mitochondria is phosphorylated by PINK1 and ubiquitinated by Parkin, linking fusion arrest to mitophagy. Dominant MFN2 mutations cause Charcot-Marie-Tooth disease type 2A, an axonal peripheral neuropathy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003924 GTPase activity | EXP PMID:28114303 MFN1 structures reveal nucleotide-triggered dimerization cri... | ACCEPT | Summary: GTPase activity. MFN2 is a dynamin-superfamily GTPase of the mitochondrial outer membrane that, with MFN1, tethers apposed mitochondria in trans and drives outer-membrane fusion in a GTP hydrolysis-dependent manner. Reason: Core molecular function; G-domain catalytic-residue mutants of MFN2 (E230A, R259A) are non-functional for mitochondrial elongation, and the activity is conserved across the mitofusin family (IBA, InterPro/RHEA IEA). Supporting Evidence: PMID:28114303 Both Mfn1E209A and Mfn1R238A, as well as the corresponding Mfn2 mutants Mfn2E230A and Mfn2R259A, failed to elongate mitochondria PMID:11181170 Formation of mitochondrial filaments and networks required a wild-type Mfn2 GTPase domain, suggesting that the Mfn2 GTPase regulates or mediates mitochondrial fusion file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0003924 GTPase activity | IBA GO_REF:0000033 | ACCEPT | Summary: GTPase activity. MFN2 is a dynamin-superfamily GTPase of the mitochondrial outer membrane that, with MFN1, tethers apposed mitochondria in trans and drives outer-membrane fusion in a GTP hydrolysis-dependent manner. Reason: Core molecular function; G-domain catalytic-residue mutants of MFN2 (E230A, R259A) are non-functional for mitochondrial elongation, and the activity is conserved across the mitofusin family (IBA, InterPro/RHEA IEA). Supporting Evidence: PMID:28114303 Both Mfn1E209A and Mfn1R238A, as well as the corresponding Mfn2 mutants Mfn2E230A and Mfn2R259A, failed to elongate mitochondria PMID:11181170 Formation of mitochondrial filaments and networks required a wild-type Mfn2 GTPase domain, suggesting that the Mfn2 GTPase regulates or mediates mitochondrial fusion file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0003924 GTPase activity | IEA GO_REF:0000120 | ACCEPT | Summary: GTPase activity. MFN2 is a dynamin-superfamily GTPase of the mitochondrial outer membrane that, with MFN1, tethers apposed mitochondria in trans and drives outer-membrane fusion in a GTP hydrolysis-dependent manner. Reason: Core molecular function; G-domain catalytic-residue mutants of MFN2 (E230A, R259A) are non-functional for mitochondrial elongation, and the activity is conserved across the mitofusin family (IBA, InterPro/RHEA IEA). Supporting Evidence: PMID:28114303 Both Mfn1E209A and Mfn1R238A, as well as the corresponding Mfn2 mutants Mfn2E230A and Mfn2R259A, failed to elongate mitochondria PMID:11181170 Formation of mitochondrial filaments and networks required a wild-type Mfn2 GTPase domain, suggesting that the Mfn2 GTPase regulates or mediates mitochondrial fusion file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0005515 protein binding | IPI PMID:16936636 MARCH-V is a novel mitofusin 2- and Drp1-binding protein abl... | REMOVE | Summary: IPI with MARCHF5 (MARCH-V), a mitochondrial E3 ligase that interacts with MFN2 and promotes MFN2-dependent elongation. Reason: Generic protein binding is uninformative; the informative aspect (binding an E3 ubiquitin ligase) is captured by the GO:0031625 annotation from the same paper. Removal does not dispute the interaction. Supporting Evidence: PMID:16936636 Immunoprecipitation studies demonstrated that MARCH-V interacts with mitofusin 2 (MFN2) and ubiquitinated forms of Drp1. |
| GO:0005515 protein binding | IPI PMID:17121834 Identification of a novel mitochondrial complex containing m... | REMOVE | Summary: IPI with STOML2 from cross-linking co-IP (abstract only cached). Reason: Generic protein binding is uninformative; STOML2 is an inner-membrane protein and the functional meaning of the association for MFN2 is unclear. |
| GO:0005515 protein binding | IPI PMID:19052620 Mitofusin 2 tethers endoplasmic reticulum to mitochondria. | MODIFY | Summary: IPI with MFN1 in the study proposing that ER-localized MFN2 tethers ER to mitochondria via homotypic and heterotypic mitofusin complexes. Reason: Protein binding is uninformative; the paper uses the MFN2-MFN1/2 trans interaction to support ER-mitochondria tethering. The tethering role is debated (some later studies found increased ER-mitochondria contact after MFN2 loss), so it is proposed here as the replacement for this row but not as a core function. Proposed replacements: mitochondrion-endoplasmic reticulum membrane tether activity Supporting Evidence: PMID:19052620 Thus, mitofusin 2 tethers ER to mitochondria, a juxtaposition required for efficient mitochondrial Ca(2+) uptake. PMID:19052620 mitofusin 2 on the ER bridges the two organelles by engaging in homotypic and heterotypic complexes with mitofusin 1 or 2 on the surface of mitochondria |
| GO:0005515 protein binding | IPI PMID:23620051 PINK1-phosphorylated mitofusin 2 is a Parkin receptor for cu... | MODIFY | Summary: IPI with PRKN: PINK1-phosphorylated MFN2 (T111/S442) binds Parkin and acts as a Parkin receptor on damaged mitochondria. Reason: More informative MF is binding of an E3 ubiquitin ligase (Parkin), which MFN2 recruits to depolarized mitochondria. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:23620051 A broad role for Mfn2 as Parkin receptor is indicated by mitochondrial abnormalities also observed with liver- and neuron-specific Mfn2 ablation PMID:23620051 simultaneous mutation of both residues (T111A/S442A) completely abrogated PINK1-stimulated interactions between Mfn2 and Parkin |
| GO:0005515 protein binding | IPI PMID:24282027 Functional interaction of Parkinson's disease-associated LRR... | REMOVE | Summary: IPI with LRRK2 by co-IP of overexpressed proteins in HEK293T cells; the paper could not confirm the interaction endogenously in brain. Reason: Uninformative protein binding with no clear functional consequence for MFN2. Supporting Evidence: PMID:24282027 An interaction of LRRK2 with Mfn2 could not be demonstrated |
| GO:0005515 protein binding | IPI PMID:25008184 IHG-1 increases mitochondrial fusion and bioenergetic functi... | REMOVE | Summary: IPI with THG1L (IHG-1), reported to increase mitochondrial fusion (abstract only cached). Reason: Generic protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:27059175 SAMM50 Affects Mitochondrial Morphology through the Associat... | REMOVE | Summary: IPI with SAMM50 (abstract only cached). Reason: Generic protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: IPI with MFN1 from proteome-scale interactome mapping (BioPlex/OpenCell). Reason: Generic protein binding is uninformative. The MFN1-MFN2 relationship is captured by the trans-tethering/fusion functions; this high-throughput interactome entry adds no functional specificity. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: IPI with MARCHF5 (MARCH-V), a mitochondrial E3 ligase that interacts with MFN2 and promotes MFN2-dependent elongation. Reason: Generic protein binding is uninformative; the informative aspect (binding an E3 ubiquitin ligase) is captured by the GO:0031625 annotation from the same paper. Removal does not dispute the interaction. Supporting Evidence: PMID:16936636 Immunoprecipitation studies demonstrated that MARCH-V interacts with mitofusin 2 (MFN2) and ubiquitinated forms of Drp1. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI with MFN1 from proteome-scale interactome mapping (BioPlex/OpenCell). Reason: Generic protein binding is uninformative. The MFN1-MFN2 relationship is captured by the trans-tethering/fusion functions; this high-throughput interactome entry adds no functional specificity. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI with MARCHF5 (MARCH-V), a mitochondrial E3 ligase that interacts with MFN2 and promotes MFN2-dependent elongation. Reason: Generic protein binding is uninformative; the informative aspect (binding an E3 ubiquitin ligase) is captured by the GO:0031625 annotation from the same paper. Removal does not dispute the interaction. Supporting Evidence: PMID:16936636 Immunoprecipitation studies demonstrated that MARCH-V interacts with mitofusin 2 (MFN2) and ubiquitinated forms of Drp1. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: IPI with MFN1 from proteome-scale interactome mapping (BioPlex/OpenCell). Reason: Generic protein binding is uninformative. The MFN1-MFN2 relationship is captured by the trans-tethering/fusion functions; this high-throughput interactome entry adds no functional specificity. |
| GO:0005525 GTP binding | IEA GO_REF:0000002 | ACCEPT | Summary: GTP binding (InterPro). Reason: Correct; MFN2 binds GTP via its dynamin-type G domain. Supporting Evidence: PMID:11181170 Formation of mitochondrial filaments and networks required a wild-type Mfn2 GTPase domain, suggesting that the Mfn2 GTPase regulates or mediates mitochondrial fusion |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: Mitochondrion (HTP, IDA, HPA, IEA). Reason: Correct, less specific than outer membrane. Supporting Evidence: PMID:34800366 mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). PMID:11181170 An internal region including a predicted bipartite transmembrane domain (TM) is sufficient to target Mfn2 to mitochondria |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Mitochondrion (HTP, IDA, HPA, IEA). Reason: Correct, less specific than outer membrane. Supporting Evidence: PMID:34800366 mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). PMID:11181170 An internal region including a predicted bipartite transmembrane domain (TM) is sufficient to target Mfn2 to mitochondria |
| GO:0005739 mitochondrion | IDA PMID:11181170 Control of mitochondrial morphology by a human mitofusin. | ACCEPT | Summary: Mitochondrion (HTP, IDA, HPA, IEA). Reason: Correct, less specific than outer membrane. Supporting Evidence: PMID:34800366 mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). PMID:11181170 An internal region including a predicted bipartite transmembrane domain (TM) is sufficient to target Mfn2 to mitochondria |
| GO:0005739 mitochondrion | IDA PMID:20871098 Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/par... | ACCEPT | Summary: Mitochondrion (HTP, IDA, HPA, IEA). Reason: Correct, less specific than outer membrane. Supporting Evidence: PMID:34800366 mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). PMID:11181170 An internal region including a predicted bipartite transmembrane domain (TM) is sufficient to target Mfn2 to mitochondria |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Mitochondrion (HTP, IDA, HPA, IEA). Reason: Correct, less specific than outer membrane. Supporting Evidence: PMID:34800366 mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). PMID:11181170 An internal region including a predicted bipartite transmembrane domain (TM) is sufficient to target Mfn2 to mitochondria |
| GO:0005741 mitochondrial outer membrane | EXP PMID:12499352 Spatial and temporal association of Bax with mitochondrial f... | ACCEPT | Summary: Mitochondrial outer membrane. MFN2 is an integral outer-membrane protein with its GTPase and coiled-coil domains in the cytosol. Reason: Core location, well supported experimentally and by IBA/ISS/IEA. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion PMID:11181170 An internal region including a predicted bipartite transmembrane domain (TM) is sufficient to target Mfn2 to mitochondria PMID:12499352 Almost complete colocalization of clusters of Mfn2-YFP with CFP-Bax was detected in apoptotic cells. |
| GO:0005741 mitochondrial outer membrane | EXP PMID:23620051 PINK1-phosphorylated mitofusin 2 is a Parkin receptor for cu... | ACCEPT | Summary: Mitochondrial outer membrane. MFN2 is an integral outer-membrane protein with its GTPase and coiled-coil domains in the cytosol. Reason: Core location, well supported experimentally and by IBA/ISS/IEA. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion PMID:11181170 An internal region including a predicted bipartite transmembrane domain (TM) is sufficient to target Mfn2 to mitochondria PMID:12499352 Almost complete colocalization of clusters of Mfn2-YFP with CFP-Bax was detected in apoptotic cells. |
| GO:0005741 mitochondrial outer membrane | EXP PMID:26214738 Regulation of mitochondrial morphology and function by stear... | ACCEPT | Summary: Mitochondrial outer membrane. MFN2 is an integral outer-membrane protein with its GTPase and coiled-coil domains in the cytosol. Reason: Core location, well supported experimentally and by IBA/ISS/IEA. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion PMID:11181170 An internal region including a predicted bipartite transmembrane domain (TM) is sufficient to target Mfn2 to mitochondria PMID:12499352 Almost complete colocalization of clusters of Mfn2-YFP with CFP-Bax was detected in apoptotic cells. |
| GO:0005741 mitochondrial outer membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrial outer membrane. MFN2 is an integral outer-membrane protein with its GTPase and coiled-coil domains in the cytosol. Reason: Core location, well supported experimentally and by IBA/ISS/IEA. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion PMID:11181170 An internal region including a predicted bipartite transmembrane domain (TM) is sufficient to target Mfn2 to mitochondria PMID:12499352 Almost complete colocalization of clusters of Mfn2-YFP with CFP-Bax was detected in apoptotic cells. |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Mitochondrial outer membrane. MFN2 is an integral outer-membrane protein with its GTPase and coiled-coil domains in the cytosol. Reason: Core location, well supported experimentally and by IBA/ISS/IEA. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion PMID:11181170 An internal region including a predicted bipartite transmembrane domain (TM) is sufficient to target Mfn2 to mitochondria PMID:12499352 Almost complete colocalization of clusters of Mfn2-YFP with CFP-Bax was detected in apoptotic cells. |
| GO:0005741 mitochondrial outer membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Mitochondrial outer membrane. MFN2 is an integral outer-membrane protein with its GTPase and coiled-coil domains in the cytosol. Reason: Core location, well supported experimentally and by IBA/ISS/IEA. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion PMID:11181170 An internal region including a predicted bipartite transmembrane domain (TM) is sufficient to target Mfn2 to mitochondria PMID:12499352 Almost complete colocalization of clusters of Mfn2-YFP with CFP-Bax was detected in apoptotic cells. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-5205649 | ACCEPT | Summary: Reactome reaction placing MFN2 at the mitochondrial outer membrane (fusion, PINK1/Parkin mitophagy, or ubiquitination reactions). Reason: Correct core location. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-5205663 | ACCEPT | Summary: Reactome reaction placing MFN2 at the mitochondrial outer membrane (fusion, PINK1/Parkin mitophagy, or ubiquitination reactions). Reason: Correct core location. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-5205673 | ACCEPT | Summary: Reactome reaction placing MFN2 at the mitochondrial outer membrane (fusion, PINK1/Parkin mitophagy, or ubiquitination reactions). Reason: Correct core location. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-9018824 | ACCEPT | Summary: Reactome reaction placing MFN2 at the mitochondrial outer membrane (fusion, PINK1/Parkin mitophagy, or ubiquitination reactions). Reason: Correct core location. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-9824888 | ACCEPT | Summary: Reactome reaction placing MFN2 at the mitochondrial outer membrane (fusion, PINK1/Parkin mitophagy, or ubiquitination reactions). Reason: Correct core location. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-9824892 | ACCEPT | Summary: Reactome reaction placing MFN2 at the mitochondrial outer membrane (fusion, PINK1/Parkin mitophagy, or ubiquitination reactions). Reason: Correct core location. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-9824894 | ACCEPT | Summary: Reactome reaction placing MFN2 at the mitochondrial outer membrane (fusion, PINK1/Parkin mitophagy, or ubiquitination reactions). Reason: Correct core location. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-9824897 | ACCEPT | Summary: Reactome reaction placing MFN2 at the mitochondrial outer membrane (fusion, PINK1/Parkin mitophagy, or ubiquitination reactions). Reason: Correct core location. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-9834070 | ACCEPT | Summary: Reactome reaction placing MFN2 at the mitochondrial outer membrane (fusion, PINK1/Parkin mitophagy, or ubiquitination reactions). Reason: Correct core location. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-9834945 | ACCEPT | Summary: Reactome reaction placing MFN2 at the mitochondrial outer membrane (fusion, PINK1/Parkin mitophagy, or ubiquitination reactions). Reason: Correct core location. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-9835009 | ACCEPT | Summary: Reactome reaction placing MFN2 at the mitochondrial outer membrane (fusion, PINK1/Parkin mitophagy, or ubiquitination reactions). Reason: Correct core location. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-9835011 | ACCEPT | Summary: Reactome reaction placing MFN2 at the mitochondrial outer membrane (fusion, PINK1/Parkin mitophagy, or ubiquitination reactions). Reason: Correct core location. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-9840807 | ACCEPT | Summary: Reactome reaction placing MFN2 at the mitochondrial outer membrane (fusion, PINK1/Parkin mitophagy, or ubiquitination reactions). Reason: Correct core location. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-992703 | ACCEPT | Summary: Reactome reaction placing MFN2 at the mitochondrial outer membrane (fusion, PINK1/Parkin mitophagy, or ubiquitination reactions). Reason: Correct core location. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0005829 cytosol | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Cytosol (ISS from rat Mfn2/HSG). Reason: MFN2 is an integral membrane protein of the outer mitochondrial membrane (and possibly ER); its soluble domains face the cytosol but the protein is not a cytosolic protein. Over-interpretation of the source. Supporting Evidence: PMID:11181170 An internal region including a predicted bipartite transmembrane domain (TM) is sufficient to target Mfn2 to mitochondria |
| GO:0007005 mitochondrion organization | IEA GO_REF:0000117 | ACCEPT | Summary: Mitochondrion organization (ARBA). Reason: Correct general parent of mitochondrial fusion. Supporting Evidence: file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0007006 mitochondrial membrane organization | IDA PMID:11181170 Control of mitochondrial morphology by a human mitofusin. | MODIFY | Summary: Mitochondrial membrane organization (IDA): MFN2 overexpression produces mitochondrial filaments and networks dependent on its GTPase domain. Reason: Correct but generic; the membrane process MFN2 performs is outer-membrane fusion. Proposed replacements: mitochondrial outer membrane fusion Supporting Evidence: PMID:11181170 Formation of mitochondrial filaments and networks required a wild-type Mfn2 GTPase domain, suggesting that the Mfn2 GTPase regulates or mediates mitochondrial fusion |
| GO:0008053 mitochondrial fusion | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrial fusion. MFN2 is a dynamin-superfamily GTPase of the mitochondrial outer membrane that, with MFN1, tethers apposed mitochondria in trans and drives outer-membrane fusion in a GTP hydrolysis-dependent manner. Reason: Core process, supported by overexpression/mutant studies, genetic interaction, ISS from mouse Mfn2, InterPro and the PANTHER IBA. Supporting Evidence: PMID:11181170 Formation of mitochondrial filaments and networks required a wild-type Mfn2 GTPase domain, suggesting that the Mfn2 GTPase regulates or mediates mitochondrial fusion PMID:23921378 we conclude that MiD49 or MiD51 cannot actively promote fusion with either Mfn partner and therefore cannot replace the function of either Mfn1 or Mfn2 file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0008053 mitochondrial fusion | IEA GO_REF:0000002 | ACCEPT | Summary: Mitochondrial fusion. MFN2 is a dynamin-superfamily GTPase of the mitochondrial outer membrane that, with MFN1, tethers apposed mitochondria in trans and drives outer-membrane fusion in a GTP hydrolysis-dependent manner. Reason: Core process, supported by overexpression/mutant studies, genetic interaction, ISS from mouse Mfn2, InterPro and the PANTHER IBA. Supporting Evidence: PMID:11181170 Formation of mitochondrial filaments and networks required a wild-type Mfn2 GTPase domain, suggesting that the Mfn2 GTPase regulates or mediates mitochondrial fusion PMID:23921378 we conclude that MiD49 or MiD51 cannot actively promote fusion with either Mfn partner and therefore cannot replace the function of either Mfn1 or Mfn2 file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0008053 mitochondrial fusion | IGI PMID:38843396 TRABD modulates mitochondrial homeostasis and tissue integri... | ACCEPT | Summary: Mitochondrial fusion. MFN2 is a dynamin-superfamily GTPase of the mitochondrial outer membrane that, with MFN1, tethers apposed mitochondria in trans and drives outer-membrane fusion in a GTP hydrolysis-dependent manner. Reason: Core process, supported by overexpression/mutant studies, genetic interaction, ISS from mouse Mfn2, InterPro and the PANTHER IBA. Supporting Evidence: PMID:11181170 Formation of mitochondrial filaments and networks required a wild-type Mfn2 GTPase domain, suggesting that the Mfn2 GTPase regulates or mediates mitochondrial fusion PMID:23921378 we conclude that MiD49 or MiD51 cannot actively promote fusion with either Mfn partner and therefore cannot replace the function of either Mfn1 or Mfn2 file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0008053 mitochondrial fusion | IMP PMID:23921378 Adaptor proteins MiD49 and MiD51 can act independently of Mf... | ACCEPT | Summary: Mitochondrial fusion. MFN2 is a dynamin-superfamily GTPase of the mitochondrial outer membrane that, with MFN1, tethers apposed mitochondria in trans and drives outer-membrane fusion in a GTP hydrolysis-dependent manner. Reason: Core process, supported by overexpression/mutant studies, genetic interaction, ISS from mouse Mfn2, InterPro and the PANTHER IBA. Supporting Evidence: PMID:11181170 Formation of mitochondrial filaments and networks required a wild-type Mfn2 GTPase domain, suggesting that the Mfn2 GTPase regulates or mediates mitochondrial fusion PMID:23921378 we conclude that MiD49 or MiD51 cannot actively promote fusion with either Mfn partner and therefore cannot replace the function of either Mfn1 or Mfn2 file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0008053 mitochondrial fusion | ISS GO_REF:0000024 | ACCEPT | Summary: Mitochondrial fusion. MFN2 is a dynamin-superfamily GTPase of the mitochondrial outer membrane that, with MFN1, tethers apposed mitochondria in trans and drives outer-membrane fusion in a GTP hydrolysis-dependent manner. Reason: Core process, supported by overexpression/mutant studies, genetic interaction, ISS from mouse Mfn2, InterPro and the PANTHER IBA. Supporting Evidence: PMID:11181170 Formation of mitochondrial filaments and networks required a wild-type Mfn2 GTPase domain, suggesting that the Mfn2 GTPase regulates or mediates mitochondrial fusion PMID:23921378 we conclude that MiD49 or MiD51 cannot actively promote fusion with either Mfn partner and therefore cannot replace the function of either Mfn1 or Mfn2 file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0008053 mitochondrial fusion | NAS PMID:11181170 Control of mitochondrial morphology by a human mitofusin. | ACCEPT | Summary: Mitochondrial fusion. MFN2 is a dynamin-superfamily GTPase of the mitochondrial outer membrane that, with MFN1, tethers apposed mitochondria in trans and drives outer-membrane fusion in a GTP hydrolysis-dependent manner. Reason: Core process, supported by overexpression/mutant studies, genetic interaction, ISS from mouse Mfn2, InterPro and the PANTHER IBA. Supporting Evidence: PMID:11181170 Formation of mitochondrial filaments and networks required a wild-type Mfn2 GTPase domain, suggesting that the Mfn2 GTPase regulates or mediates mitochondrial fusion PMID:23921378 we conclude that MiD49 or MiD51 cannot actively promote fusion with either Mfn partner and therefore cannot replace the function of either Mfn1 or Mfn2 file:human/MFN2/MFN2-uniprot.txt Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion |
| GO:0009060 aerobic respiration | IMP PMID:19889647 Phenotypic spectrum of MFN2 mutations in the Spanish populat... | KEEP AS NON CORE | Summary: Aerobic respiration (IMP): fibroblasts from a CMT2A patient carrying MFN2 R468H show a mitochondrial coupling defect. Reason: Respiratory defects in MFN2-mutant cells are a downstream consequence of impaired mitochondrial dynamics/quality control; MFN2 is not a component of the respiratory machinery. Supporting Evidence: PMID:19889647 The bioenergetic studies in fibroblasts show typical results of MFN2 patients with a mitochondrial coupling defect (ATP/O) |
| GO:0015630 microtubule cytoskeleton | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Microtubule cytoskeleton (IEA, Ensembl Compara transfer from mouse). Reason: MFN2 associates with the Miro/TRAK mitochondrial transport machinery but is an outer-membrane protein, not a component of the microtubule cytoskeleton. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: Membrane (InterPro). Reason: Correct but general; MFN2 is an integral outer-membrane protein. Supporting Evidence: PMID:11181170 An internal region including a predicted bipartite transmembrane domain (TM) is sufficient to target Mfn2 to mitochondria |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:16936636 MARCH-V is a novel mitofusin 2- and Drp1-binding protein abl... | KEEP AS NON CORE | Summary: Ubiquitin protein ligase binding (IPI with MARCHF5). Reason: Supported; MFN2 binds the E3 ligases MARCHF5 and (after PINK1 phosphorylation) Parkin, and is a ubiquitination substrate. Relevant to its regulation and mitophagy role rather than its core fusion activity. Supporting Evidence: PMID:16936636 Immunoprecipitation studies demonstrated that MARCH-V interacts with mitofusin 2 (MFN2) and ubiquitinated forms of Drp1. PMID:16936636 it is conceivable that MARCH-V does not have the intrinsic ability to fuse mitochondria and that its effect is exerted through MFN2 activity |
| GO:0034497 protein localization to phagophore assembly site | IDA PMID:23455425 Autophagosomes form at ER-mitochondria contact sites. | KEEP AS NON CORE | Summary: Protein localization to phagophore assembly site (IDA): MFN2-dependent ER-mitochondria contacts are needed for ATG14 puncta formation (abstract only cached). Reason: Effect of disrupting contact sites (including MFN2 knockdown) on autophagosome biogenesis; MFN2 acts indirectly by maintaining ER-mitochondria contacts. Supporting Evidence: PMID:23455425 Disruption of the ER-mitochondria contact site prevents the formation of ATG14 puncta. |
| GO:0046580 negative regulation of Ras protein signal transduction | IDA PMID:15322553 Dysregulation of HSG triggers vascular proliferative disorde... | KEEP AS NON CORE | Summary: Negative regulation of Ras protein signal transduction (IDA): HSG/MFN2 suppresses VSMC proliferation by inhibiting Ras-ERK signalling, via a p21ras signature motif. Reason: Reported (rat HSG) and independent of fusion; peripheral to the core role and not widely replicated. Supporting Evidence: PMID:15322553 Deletion of the p21(ras) signature motif, but not the mitochondrial targeting domain, abolished HSG-induced growth arrest, indicating that rHSG-induced anti-proliferation was independent of mitochondrial fusion. |
| GO:0048662 negative regulation of smooth muscle cell proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of smooth muscle cell proliferation (ISS from rat HSG). Reason: Consistent with the HSG anti-proliferative studies; non-core. Supporting Evidence: PMID:15322553 Deletion of the p21(ras) signature motif, but not the mitochondrial targeting domain, abolished HSG-induced growth arrest, indicating that rHSG-induced anti-proliferation was independent of mitochondrial fusion. file:human/MFN2/MFN2-uniprot.txt Plays an important role in the regulation of vascular smooth muscle cell proliferation (By similarity). |
| GO:0051646 mitochondrion localization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Mitochondrion localization (IBA). Reason: MFN2 interacts with Miro/TRAK and is required for axonal mitochondrial transport in neurons; secondary to its fusion role. |
| GO:0061734 type 2 mitophagy | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Type 2 (PINK1/Parkin) mitophagy (ISS/IEA from mouse): PINK1-phosphorylated MFN2 serves as a Parkin receptor. Reason: Supported by the mouse cardiomyocyte study; MFN2 is also a major Parkin ubiquitination substrate whose removal segregates damaged mitochondria. Non-core relative to fusion. Supporting Evidence: PMID:23620051 A broad role for Mfn2 as Parkin receptor is indicated by mitochondrial abnormalities also observed with liver- and neuron-specific Mfn2 ablation PMID:20871098 An increase in the ubiquitination of a number of mitochondrial proteins correlates with the induction of mitophagy, including the fusion factors of the outer membrane, mitofusins 1 (MFN-1) and 2 (MFN-2). file:human/MFN2/MFN2-uniprot.txt Is required for PRKN recruitment to dysfunctional mitochondria (PubMed:23620051). |
| GO:0061734 type 2 mitophagy | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Type 2 (PINK1/Parkin) mitophagy (ISS/IEA from mouse): PINK1-phosphorylated MFN2 serves as a Parkin receptor. Reason: Supported by the mouse cardiomyocyte study; MFN2 is also a major Parkin ubiquitination substrate whose removal segregates damaged mitochondria. Non-core relative to fusion. Supporting Evidence: PMID:23620051 A broad role for Mfn2 as Parkin receptor is indicated by mitochondrial abnormalities also observed with liver- and neuron-specific Mfn2 ablation PMID:20871098 An increase in the ubiquitination of a number of mitochondrial proteins correlates with the induction of mitophagy, including the fusion factors of the outer membrane, mitofusins 1 (MFN-1) and 2 (MFN-2). file:human/MFN2/MFN2-uniprot.txt Is required for PRKN recruitment to dysfunctional mitochondria (PubMed:23620051). |
| GO:0120162 positive regulation of cold-induced thermogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of cold-induced thermogenesis (ISS/IEA from mouse): BAT-specific Mfn2 knockout mice cannot maintain body temperature on cold exposure. Reason: Tissue-specific physiological consequence of mitochondrial dynamics in brown fat; non-core. Supporting Evidence: PMID:28539390 Acute cold exposure (4°C for 7 h) revealed an inability of BAT‐Mfn2‐KO mice to maintain body temperature after 3 h of exposure |
| GO:0120162 positive regulation of cold-induced thermogenesis | ISS PMID:28539390 Mfn2 deletion in brown adipose tissue protects from insulin ... | KEEP AS NON CORE | Summary: Positive regulation of cold-induced thermogenesis (ISS/IEA from mouse): BAT-specific Mfn2 knockout mice cannot maintain body temperature on cold exposure. Reason: Tissue-specific physiological consequence of mitochondrial dynamics in brown fat; non-core. Supporting Evidence: PMID:28539390 Acute cold exposure (4°C for 7 h) revealed an inability of BAT‐Mfn2‐KO mice to maintain body temperature after 3 h of exposure |
| GO:1904707 positive regulation of vascular associated smooth muscle cell proliferation | IMP PMID:27640178 Upregulated miR-17 Regulates Hypoxia-Mediated Human Pulmonar... | KEEP AS NON CORE | Summary: Positive regulation of vascular associated smooth muscle cell proliferation (IMP in hPASMC with miR-17 manipulation). Reason: The study found MFN2 required for miR-17-mediated regulation of PASMC proliferation; note that the sign is at odds with the anti-proliferative HSG literature (GO:0048662), so the regulatory role in proliferation is context dependent and peripheral. Supporting Evidence: PMID:27640178 suggesting that MFN2 is required for miR-17-mediated regulation of hPASMC proliferation and apoptosis |
| GO:1905461 positive regulation of vascular associated smooth muscle cell apoptotic process | IMP PMID:27640178 Upregulated miR-17 Regulates Hypoxia-Mediated Human Pulmonar... | KEEP AS NON CORE | Summary: Positive regulation of vascular associated smooth muscle cell apoptotic process (IMP in hPASMC). Reason: Cell-type-specific phenotype; non-core. Supporting Evidence: PMID:27640178 suggesting that MFN2 is required for miR-17-mediated regulation of hPASMC proliferation and apoptosis |
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Download this section (compressed HTML)Q: Does MFN2 act as a direct ER-mitochondria tether in vivo, or do its effects on contact sites arise indirectly from altered mitochondrial dynamics (the de Brito/Scorrano versus Filadi/Pozzan controversy)?
Q: Which MFN2-specific functions (Parkin receptor, ER contacts, Miro-dependent transport) explain why CMT2A is caused by MFN2 rather than MFN1 mutations?
Experiment: Acute, degron-mediated depletion of MFN2 combined with quantitative cryo-ET of ER-mitochondria contacts to separate direct tethering from secondary effects of altered mitochondrial morphology.
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