id: Q8C6I2 gene_symbol: Sdhaf2 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:10090 label: Mus musculus description: >- Sdhaf2 (also called Sdh5 or Pgl2) encodes succinate dehydrogenase assembly factor 2, a small nuclear-encoded protein of the mitochondrial matrix. Isoform 1 (Q8C6I2-1) has 164 residues with a predicted N-terminal mitochondrial transit peptide (residues 1-27) and a single Sdh5/SdhE domain (Pfam PF03937). It belongs to the SDHAF2/Sdh5/SdhE family (PANTHER PTHR12469:SF2), shared with human SDHAF2, yeast Sdh5 and bacterial SdhE. Members of this family are assembly factors for succinate dehydrogenase (respiratory complex II). They bind the flavoprotein subunit SDHA and, together with a dicarboxylate, position the flavin and capping domains of SDHA so that FAD can be covalently attached (flavinylation), a step needed for a catalytically competent complex II. Sdhaf2 is not a subunit of the mature enzyme and has no catalytic activity of its own. The flavinylation mechanism has been shown for the human, yeast and bacterial orthologs, not for the mouse protein. Mouse evidence places Sdhaf2 in mitochondria, with a cytosolic pre-import pool in myotubes. In mouse skeletal muscle and C2C12 myocytes, the mitochondrial fission GTPase Drp1 interacts with Sdhaf2 and promotes its mitochondrial translocation. Loss of Drp1 lowers mitochondrial Sdhaf2 and selectively reduces complex II assembly, and overexpressing Sdhaf2 restores succinate-dependent respiration in Drp1-deficient myocytes. One study of Sdhaf2-knockout mice and lung cancer cells linked loss of the protein to epithelial-mesenchymal transition through GSK-3beta/beta-catenin signalling. This is a context-dependent role, separate from complex II maturation. alternative_products: - name: '1' id: Q8C6I2-1 - name: '2' id: Q8C6I2-2 sequence_note: VSP_026634 - name: '3' id: Q8C6I2-3 sequence_note: VSP_026633 existing_annotations: - term: id: GO:0003674 label: molecular_function evidence_type: ND original_reference_id: GO_REF:0000015 qualifier: enables review: summary: >- Root molecular function ND annotation: when it was made, no molecular function had been curated for this gene product from literature. action: ACCEPT reason: >- ACCEPT under the ND acceptance rule (projects/NO_DATA.md). The evidence this review cites for the molecular function is inferred (from orthologs, family membership or sequence features) or comes from other species; none of it is literature on this gene product in this species. This was judged from the review's own content during the NO_DATA re-action pass, not from a new literature search. Earlier action: MODIFY. Re-checked 2026-10-31: the chaperone activity rests on human and yeast SDHAF2/SDH5 (PMID:32887801, PMID:19628817); the mouse study cited (PMID:38569044) shows a role in complex II assembly, not the activity. The term the earlier MODIFY proposed, protein folding chaperone, is kept as its own NEW row. The gene's notes, which list the mouse-specific literature found, record that no molecular activity (SDHA binding, flavinylation or chaperone activity) has been established in mouse. supported_by: - reference_id: file:mouse/Sdhaf2__Q8C6I2/Sdhaf2__Q8C6I2-notes.md supporting_text: 'Not established in mouse: SDHA binding, covalent flavinylation of SDHA, and chaperone activity.' nd_case: INFERABLE - term: id: GO:0005730 label: nucleolus evidence_type: ISO original_reference_id: GO_REF:0000119 qualifier: located_in supporting_entities: - UniProtKB:Q9NX18 review: summary: >- Automated mouse-human orthology transfer of a nucleolar localization for human SDHAF2. The current human GOA set no longer carries a nucleolus annotation; the human review records only mitochondrial and matrix locations. Sdhaf2 has a mitochondrial transit peptide and works on SDHA inside the matrix. No mouse or family evidence supports a nucleolar pool. action: MARK_AS_OVER_ANNOTATED reason: >- The only likely source is a single antibody-based human observation, which is not reproduced for mouse. It conflicts with the matrix function of the protein and with the mouse fractionation data, which show cytosolic and mitochondrial pools only. It should not be propagated as a mouse location. propagation_review: root_cause: SOURCE_STALE_OR_MISSING failure_modes: - COMPARTMENT_OR_COMPLEX_MISMATCH supported_by: - reference_id: file:mouse/Sdhaf2__Q8C6I2/Sdhaf2__Q8C6I2-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix" - term: id: GO:0005739 label: mitochondrion evidence_type: HDA original_reference_id: PMID:18614015 qualifier: located_in review: summary: >- Mouse experimental (HDA) evidence. Sdhaf2 was in the MitoCarta compendium, built from mass spectrometry of purified mitochondria from 14 mouse tissues. This is direct mouse evidence that the protein is mitochondrial. action: MODIFY reason: >- The term is correct but general. The protein sits in the mitochondrial matrix, a term this gene already carries (GO:0005759, by UniRule/SubCell and by ISO from the human experimental annotation). This MODIFY refines the location; it does not dispute the MitoCarta evidence. proposed_replacement_terms: - id: GO:0005759 label: mitochondrial matrix supported_by: - reference_id: PMID:18614015 supporting_text: >- The resulting compendium consists of 1098 genes ( Figure 1 ) and their protein expression across 14 mouse tissues. - reference_id: PMID:38569044 supporting_text: Drp1 interacts with Sdhaf2 and enhances its mitochondrial translocation. - term: id: GO:0005739 label: mitochondrion evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - AGI_LocusCode:AT5G51040 - PANTHER:PTN000279729 - SGD:S000005432 - UniProtKB:Q9NX18 review: summary: >- PAINT IBD at the eukaryotic node PTN000279729 (taxon 2759), seeded from Arabidopsis SDHAF2, yeast Sdh5 and human SDHAF2. Mouse Q8C6I2 is in subfamily PTHR12469:SF2, which descends from this node. The localization is sound and is confirmed in mouse by HDA. action: MODIFY reason: >- Kept consistent with the other mitochondrion rows. The term is correct but less specific than the supported matrix location (GO:0005759), which the gene already carries. proposed_replacement_terms: - id: GO:0005759 label: mitochondrial matrix propagation_review: root_cause: NO_FAILURE_CORE failure_modes: - GRANULARITY_MISMATCH supported_by: - reference_id: file:mouse/Sdhaf2__Q8C6I2/Sdhaf2__Q8C6I2-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix" - term: id: GO:0005739 label: mitochondrion evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in supporting_entities: - UniProtKB:Q9NX18 - ensembl:ENSP00000301761 - InterPro:IPR028882 review: summary: >- Combined electronic annotation from orthology and the SDHAF2 InterPro entry (IPR028882). Correct. action: MODIFY reason: >- Correct but general. The specific supported location is the mitochondrial matrix (GO:0005759), which the gene already carries. proposed_replacement_terms: - id: GO:0005759 label: mitochondrial matrix supported_by: - reference_id: file:mouse/Sdhaf2__Q8C6I2/Sdhaf2__Q8C6I2-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix" - term: id: GO:0005739 label: mitochondrion evidence_type: ISO original_reference_id: GO_REF:0000119 qualifier: located_in supporting_entities: - UniProtKB:Q9NX18 review: summary: >- Orthology transfer from human SDHAF2 (IDA, HPA and founding-study evidence). Correct for mouse and independently confirmed by mouse proteomics and fractionation. action: MODIFY reason: >- Correct but general. The specific supported location is the mitochondrial matrix (GO:0005759), which the gene already carries. proposed_replacement_terms: - id: GO:0005759 label: mitochondrial matrix propagation_review: root_cause: NO_FAILURE_CORE failure_modes: - GRANULARITY_MISMATCH supported_by: - reference_id: PMID:38569044 supporting_text: Drp1 interacts with Sdhaf2 and enhances its mitochondrial translocation. - term: id: GO:0005739 label: mitochondrion evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in supporting_entities: - UniProtKB:Q9NX18 review: summary: >- UniProt curator transfer by sequence similarity from human SDHAF2. Correct. action: MODIFY reason: >- Correct but general. The specific supported location is the mitochondrial matrix (GO:0005759), which the gene already carries. proposed_replacement_terms: - id: GO:0005759 label: mitochondrial matrix supported_by: - reference_id: file:mouse/Sdhaf2__Q8C6I2/Sdhaf2__Q8C6I2-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix" - term: id: GO:0005759 label: mitochondrial matrix evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0170 - UniRule:UR000369524 review: summary: >- UniRule/SubCell electronic annotation of a matrix location. This is the specific, correct site of action: SDHA flavinylation happens in the matrix before SDHA joins the inner-membrane anchor subunits. The evidence is family-level (HAMAP MF_03057) and the human EXP annotation; no mouse sub-mitochondrial fractionation exists. action: ACCEPT supported_by: - reference_id: file:mouse/Sdhaf2__Q8C6I2/Sdhaf2__Q8C6I2-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix" - term: id: GO:0005759 label: mitochondrial matrix evidence_type: ISO original_reference_id: GO_REF:0000119 qualifier: located_in supporting_entities: - UniProtKB:Q9NX18 review: summary: >- Orthology transfer of the human experimental matrix localization (PMID:19628817, EXP). Correct, core location; the human and mouse proteins are in the same subfamily (SF2). action: ACCEPT supported_by: - reference_id: file:mouse/Sdhaf2__Q8C6I2/Sdhaf2__Q8C6I2-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix" - term: id: GO:0005829 label: cytosol evidence_type: ISO original_reference_id: GO_REF:0000119 qualifier: located_in supporting_entities: - UniProtKB:Q9NX18 review: summary: >- Orthology transfer of a cytosolic localization. In mouse, Sdhaf2 is found in the cytosolic fraction of C2C12 myotubes, and its mitochondrial import there depends on Drp1. A cytosolic pool therefore exists in mouse cells. It appears to be the pre-import precursor, not the site where Sdhaf2 acts on SDHA. action: KEEP_AS_NON_CORE reason: >- The location is supported (mouse fractionation), but it is peripheral to the core function, which is carried out in the matrix. supported_by: - reference_id: PMID:38569044 supporting_text: >- Immunoblot of Sdhaf2 in cytosolic and mitochondrial fractions of control (Scr) and Drp1KD myotubes - term: id: GO:0006099 label: tricarboxylic acid cycle evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - PANTHER:PTN000279729 - SGD:S000005432 review: summary: >- PAINT IBD at PTN000279729, seeded only from yeast Sdh5. The PAINT curators made a deliberate placement, and mouse Sdhaf2 is inside the clade. However, Sdhaf2 performs no step of the TCA cycle. It matures SDHA before the enzyme that carries out the succinate-to-fumarate step is assembled. The yeast donor annotation reflects necessity (sdh5 mutants lack SDH activity), not participation. action: MARK_AS_OVER_ANNOTATED reason: >- Assembly factor versus catalytic enzyme (role conflation). Sdhaf2 acts upstream of the TCA cycle by enabling complex II maturation. The informative process is complex II assembly (GO:0034553). This is consistent with the treatment of the same IBA on the human ortholog. propagation_review: root_cause: PROPAGATION_BAD failure_modes: - ROLE_CONFLATION supported_by: - reference_id: file:mouse/Sdhaf2__Q8C6I2/Sdhaf2__Q8C6I2-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: "Required for flavinylation (covalent" - term: id: GO:0006121 label: mitochondrial electron transport, succinate to ubiquinone evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - PANTHER:PTN000279729 - SGD:S000005432 - UniProtKB:Q9NX18 review: summary: >- PAINT IBD at PTN000279729. Electron transfer from succinate to ubiquinone is carried out by the assembled complex II (SDHA-D). Sdhaf2 is required for complex II to form, but it does not transfer electrons and is not part of the mature complex. action: MARK_AS_OVER_ANNOTATED reason: >- Necessity, not participation. The electron transport step is performed by SDHA/SDHB/SDHC/SDHD. Sdhaf2's contribution is upstream, through complex II assembly and SDHA flavinylation. propagation_review: root_cause: PROPAGATION_BAD failure_modes: - ROLE_CONFLATION supported_by: - reference_id: file:mouse/Sdhaf2__Q8C6I2/Sdhaf2__Q8C6I2-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: "Plays an essential role in the assembly of succinate" - term: id: GO:0006121 label: mitochondrial electron transport, succinate to ubiquinone evidence_type: IEA original_reference_id: GO_REF:0000104 qualifier: involved_in supporting_entities: - UniRule:UR000369524 review: summary: >- UniRule electronic transfer of the same process term. Same reasoning as the IBA row: an assembly factor does not carry out the electron transport step. action: MARK_AS_OVER_ANNOTATED reason: >- Consistent with the IBA and ISO rows for this term. supported_by: - reference_id: file:mouse/Sdhaf2__Q8C6I2/Sdhaf2__Q8C6I2-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: "Plays an essential role in the assembly of succinate" - term: id: GO:0006121 label: mitochondrial electron transport, succinate to ubiquinone evidence_type: ISO original_reference_id: GO_REF:0000119 qualifier: involved_in supporting_entities: - UniProtKB:Q9NX18 review: summary: >- Orthology transfer of the same process term. Same reasoning as the IBA row. action: MARK_AS_OVER_ANNOTATED reason: >- Consistent with the IBA and IEA rows for this term. In mouse, Sdhaf2 restoration in Drp1-knockdown myocytes increased succinate-dependent respiratory control. This shows that Sdhaf2 is needed for complex II-linked respiration, not that it transports electrons. propagation_review: root_cause: PROPAGATION_BAD failure_modes: - ROLE_CONFLATION supported_by: - reference_id: PMID:38569044 supporting_text: >- Moreover, we observed that Sdhaf2 overexpression significantly increased the RCR in Drp1KD myocytes, but only in the presence of succinate, not pyruvate - term: id: GO:0006470 label: protein dephosphorylation evidence_type: IMP original_reference_id: PMID:23983127 qualifier: acts_upstream_of_or_within review: summary: >- MGI IMP (acts_upstream_of_or_within) from the lung-cancer study. In that study, the Sdhaf2-GSK-3beta interaction was associated with loss of the inhibitory phosphate on GSK-3beta Ser-9. Sdhaf2 has no phosphatase domain and the phosphatase involved was not identified. The effect on GSK-3beta phosphorylation is indirect and context-dependent. The cached full text is partial (results and figures are missing), so we cannot see which experiment in mouse tissue the curator used. action: KEEP_AS_NON_CORE reason: >- Kept, deferring to the MGI curator who read the full paper. The acts_upstream_of_or_within qualifier already records that the role is indirect. This is peripheral to the mitochondrial assembly-factor function, and the mechanism linking a matrix protein to cytosolic GSK-3beta is unresolved. supported_by: - reference_id: PMID:23983127 supporting_text: >- The physical interaction between SDH5 and GSK-3β facilitates GSK-3β activation through Ser-9 dephosphorylation - term: id: GO:0006470 label: protein dephosphorylation evidence_type: ISO original_reference_id: GO_REF:0000008 qualifier: acts_upstream_of_or_within supporting_entities: - UniProtKB:Q9NX18 review: summary: >- MGI orthology transfer of the human IGI annotation from the same paper (PMID:23983127). Same assessment as the IMP row. action: KEEP_AS_NON_CORE reason: >- Consistent with the IMP row. This is an indirect, cancer-context regulatory effect. supported_by: - reference_id: PMID:23983127 supporting_text: >- The physical interaction between SDH5 and GSK-3β facilitates GSK-3β activation through Ser-9 dephosphorylation - term: id: GO:0010719 label: negative regulation of epithelial to mesenchymal transition evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in supporting_entities: - ARBA:ARBA00085215 review: summary: >- ARBA machine-learning annotation that repeats the experimental annotation from PMID:23983127. The underlying finding is real but context-dependent, and is kept as non-core with the experimental rows. action: KEEP_AS_NON_CORE reason: >- Consistent with the IMP and ISO rows for this term. The ARBA rule adds no independent support. supported_by: - reference_id: PMID:23983127 supporting_text: >- In SDH5 knock-out mice, lung epithelial cells exhibited elevated mesenchymal markers, which is characteristic of EMT. - term: id: GO:0010719 label: negative regulation of epithelial to mesenchymal transition evidence_type: IMP original_reference_id: PMID:23983127 qualifier: acts_upstream_of_or_within review: summary: >- Mouse experimental evidence: lung epithelial cells of SDH5 (Sdhaf2) knockout mice had higher levels of mesenchymal markers. Loss of SDH5 also caused EMT in human lung cancer cells and xenografts. This is a genuine mouse phenotype. Whether it follows from loss of complex II and succinate accumulation, or from a separate GSK-3beta interaction, is not resolved. action: KEEP_AS_NON_CORE reason: >- A cancer and tissue-context regulatory phenotype, recorded with the acts_upstream_of_or_within qualifier. It is peripheral to the core mitochondrial function and probably indirect. supported_by: - reference_id: PMID:23983127 supporting_text: >- In SDH5 knock-out mice, lung epithelial cells exhibited elevated mesenchymal markers, which is characteristic of EMT. - term: id: GO:0010719 label: negative regulation of epithelial to mesenchymal transition evidence_type: ISO original_reference_id: GO_REF:0000008 qualifier: acts_upstream_of_or_within supporting_entities: - UniProtKB:Q9NX18 review: summary: >- Orthology transfer of the human IMP annotation from the same paper. Same assessment. action: KEEP_AS_NON_CORE reason: >- Consistent with the IMP row for this term. supported_by: - reference_id: PMID:23983127 supporting_text: >- loss of succinate dehydrogenase 5 (SDH5) expression initiates epithelial-mesenchymal transition (EMT) - term: id: GO:0018293 label: protein-FAD linkage evidence_type: ISO original_reference_id: GO_REF:0000119 qualifier: involved_in supporting_entities: - UniProtKB:Q9NX18 review: summary: >- Orthology transfer of the human IMP: SDH5 is required for flavination of the SDH flavoprotein. The mouse protein is in the same subfamily (SF2) as human SDHAF2, and this role is conserved from bacterial SdhE to yeast Sdh5 and human SDHAF2. Sdhaf2 contributes structurally to this step by positioning the SDHA flavin and capping domains. Covalent flavinylation of SDHA has not been measured directly in mouse. action: ACCEPT reason: >- Core process, inferred for mouse through the subfamily. GO:0018293 is the precise term for the covalent FAD attachment step that Sdhaf2 enables. supported_by: - reference_id: PMID:19628817 supporting_text: >- Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination (incorporation of the flavin adenine dinucleotide cofactor) - reference_id: PMID:32887801 supporting_text: >- works in synergy with SDHAF2 to properly orient the flavin and capping domains of SDHA - term: id: GO:0018293 label: protein-FAD linkage evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in supporting_entities: - UniProtKB:Q9NX18 review: summary: >- UniProt curator similarity transfer of the same core process from human SDHAF2. Same assessment as the ISO row. action: ACCEPT reason: >- Core process, inferred through the subfamily. Consistent with the ISO row. supported_by: - reference_id: file:mouse/Sdhaf2__Q8C6I2/Sdhaf2__Q8C6I2-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: "Required for flavinylation (covalent" - term: id: GO:0034553 label: mitochondrial respiratory chain complex II assembly evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - PANTHER:PTN000279729 - SGD:S000005432 - UniProtKB:Q9NX18 review: summary: >- PAINT IBD at the eukaryotic node PTN000279729, seeded from yeast Sdh5 and human SDHAF2. Mouse Sdhaf2 (SF2) descends from this node. Mouse data agree: Drp1 deficiency lowers mitochondrial Sdhaf2 and selectively reduces complex II assembly on BN-PAGE, and Sdhaf2 restoration normalizes complex II activity in Drp1-knockdown myocytes. action: ACCEPT reason: >- Core process. It is placed phylogenetically and supported by mouse functional data in muscle and myocytes (PMID:38569044). The in vivo perturbation in that study was Drp1, not Sdhaf2 itself. supported_by: - reference_id: PMID:38569044 supporting_text: >- Muscle Drp1-KD reduced complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). - reference_id: file:mouse/Sdhaf2__Q8C6I2/Sdhaf2__Q8C6I2-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: "Plays an essential role in the assembly of succinate" - term: id: GO:0034553 label: mitochondrial respiratory chain complex II assembly evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in supporting_entities: - UniProtKB:Q9NX18 - ensembl:ENSP00000301761 review: summary: >- Ensembl Compara orthology transfer of the same core process from human SDHAF2. Correct. action: ACCEPT reason: >- Core process. Consistent with the IBA and ISO rows. supported_by: - reference_id: file:mouse/Sdhaf2__Q8C6I2/Sdhaf2__Q8C6I2-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: "Plays an essential role in the assembly of succinate" - term: id: GO:0034553 label: mitochondrial respiratory chain complex II assembly evidence_type: ISO original_reference_id: GO_REF:0000119 qualifier: involved_in supporting_entities: - UniProtKB:Q9NX18 review: summary: >- Orthology transfer of the human IDA (SDHA-SDHAF2 structure, PMID:32887801) for complex II assembly. Correct, and agrees with the mouse muscle data. action: ACCEPT reason: >- Core process. supported_by: - reference_id: PMID:38569044 supporting_text: Restoration of Sdhaf2 normalized complex II - term: id: GO:0090090 label: negative regulation of canonical Wnt signaling pathway evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in supporting_entities: - ARBA:ARBA00027950 review: summary: >- ARBA machine-learning annotation that repeats the experimental annotation from PMID:23983127, which reported effects on GSK-3beta/beta-catenin signalling. Kept as non-core with the experimental rows. action: KEEP_AS_NON_CORE reason: >- Consistent with the IMP and ISO rows for this term. The ARBA rule adds no independent support. supported_by: - reference_id: PMID:23983127 supporting_text: >- SDH5 functions as a negative regulator of Wnt-β-catenin signaling - term: id: GO:0090090 label: negative regulation of canonical Wnt signaling pathway evidence_type: IMP original_reference_id: PMID:23983127 qualifier: acts_upstream_of_or_within review: summary: >- MGI IMP from the lung cancer/knockout mouse study. Loss of SDH5 increased nuclear beta-catenin accumulation and beta-catenin transcriptional activity. The effect is reported as mediated through GSK-3beta. It is indirect and context-dependent, and the cached full text does not include the figures that show which data are from mouse. action: KEEP_AS_NON_CORE reason: >- Kept, deferring to the curator who read the full text. The qualifier records an upstream, indirect role. This is not the core function. supported_by: - reference_id: PMID:23983127 supporting_text: >- SDH5 functions as a negative regulator of Wnt-β-catenin signaling - term: id: GO:0090090 label: negative regulation of canonical Wnt signaling pathway evidence_type: ISO original_reference_id: GO_REF:0000008 qualifier: acts_upstream_of_or_within supporting_entities: - UniProtKB:Q9NX18 review: summary: >- Orthology transfer of the human IGI annotation from the same paper. Same assessment. action: KEEP_AS_NON_CORE reason: >- Consistent with the IMP row for this term. supported_by: - reference_id: PMID:23983127 supporting_text: >- SDH5 functions as a negative regulator of Wnt-β-catenin signaling - term: id: GO:0044183 label: protein folding chaperone evidence_type: ISO original_reference_id: PMID:32887801 qualifier: enables review: summary: Inferred protein folding chaperone for this gene product, proposed during the NO_DATA re-action pass. action: NEW reason: 'Protein folding chaperone is inferred for this gene product (ISO), not shown for it experimentally; the ND row for the aspect therefore stays (projects/NO_DATA.md). The root MF term says nothing. An orthology-grounded MF is available: protein folding chaperone (GO:0044183), as used for the human SF2 subfamily member Q9NX18 on structural (IDA) evidence. For mouse this is an inference from the subfamily, not a mouse experiment. The UniRule/HAMAP statement on the mouse record (ECO:0000255|HAMAP-Rule:MF_03057) also describes Sdhaf2 as required for SDHA flavinylation.' supported_by: - reference_id: PMID:32887801 supporting_text: works in synergy with SDHAF2 to properly orient the flavin and capping domains of SDHA - reference_id: file:mouse/Sdhaf2__Q8C6I2/Sdhaf2__Q8C6I2-uniprot.txt record_section: ["CC:FUNCTION"] supporting_text: Required for flavinylation (covalent references: - id: GO_REF:0000008 title: Gene Ontology annotation by the MGI curatorial staff, curated orthology findings: [] - id: GO_REF:0000015 title: Use of the ND evidence code for Gene Ontology (GO) terms findings: [] - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000104 title: Electronic Gene Ontology annotations created by transferring manual GO annotations between related proteins based on shared sequence features findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000119 title: Automated transfer of experimentally-verified manual GO annotation data to mouse-human orthologs findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:18614015 title: A mitochondrial protein compendium elucidates complex I disease biology. findings: - statement: >- MitoCarta. Mass spectrometry of mitochondria from 14 mouse tissues, combined with other localization datasets, puts Sdhaf2 in the mitochondrial proteome (mouse HDA evidence). supporting_text: >- The resulting compendium consists of 1098 genes ( Figure 1 ) and their protein expression across 14 mouse tissues. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- Full text cached. High-throughput mouse evidence for mitochondrial localization; it does not address Sdhaf2 function. - id: PMID:23983127 title: Succinate dehydrogenase 5 (SDH5) regulates glycogen synthase kinase 3β-β-catenin-mediated lung cancer metastasis. findings: - statement: >- SDH5 (Sdhaf2) knockout mice show more mesenchymal markers in lung epithelium. In lung cancer cells, loss of SDH5 promotes EMT and metastasis, which the authors attribute to an SDH5-GSK-3beta interaction that promotes GSK-3beta Ser-9 dephosphorylation and limits nuclear beta-catenin. supporting_text: >- In SDH5 knock-out mice, lung epithelial cells exhibited elevated mesenchymal markers, which is characteristic of EMT. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- Source of the MGI IMP rows. The cache holds the abstract, introduction and discussion; the results and figure legends are missing. The only mouse-specific statement visible is the knockout lung EMT-marker phenotype. The signalling mechanism comes mostly from human cell lines. The role is context-dependent and not the core function. - id: PMID:19628817 title: SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. findings: - statement: >- Yeast and human Sdh5/SDHAF2 bind the SDH catalytic subunit and are required for flavination of SDHA/Sdh1 and for SDH-dependent respiration. Basis of the human flavinylation and matrix annotations transferred to mouse. supporting_text: >- Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination (incorporation of the flavin adenine dinucleotide cofactor) reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Abstract-only in cache. Founding study for the family function; ortholog evidence (yeast, human), not a mouse experiment. - id: PMID:32887801 title: The roles of SDHAF2 and dicarboxylate in covalent flavinylation of SDHA, the human complex II flavoprotein. findings: - statement: >- The human SDHA-SDHAF2 crystal structure shows that SDHAF2 and a dicarboxylate together orient the SDHA flavin and capping domains to allow covalent FAD attachment. SDHAF2 acts as a non-catalytic chaperone. supporting_text: >- works in synergy with SDHAF2 to properly orient the flavin and capping domains of SDHA reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Abstract-only in cache. Human SF2 ortholog; the mechanistic basis for the inferred mouse MF. - id: PMID:38569044 title: Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria. findings: - statement: >- In mouse skeletal muscle and C2C12 myocytes, Drp1 interacts with Sdhaf2 and promotes its mitochondrial translocation. Drp1 deficiency lowers mitochondrial (not total) Sdhaf2 and selectively reduces complex II assembly and activity. Sdhaf2 overexpression restores succinate-dependent respiratory control, fatty-acid oxidation and insulin action in Drp1-knockdown myocytes. supporting_text: >- Muscle Drp1-KD reduced complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Full text cached. This is the main mouse-specific functional evidence for Sdhaf2 in complex II assembly. The primary perturbation was Drp1; the Sdhaf2 gain-of-function rescue was done in cultured murine myocytes. The Drp1-Sdhaf2 binding assay used recombinant human proteins, while the proximity ligation was done in mouse C2C12 cells. - id: file:mouse/Sdhaf2__Q8C6I2/Sdhaf2__Q8C6I2-uniprot.txt title: UniProt Swiss-Prot record Q8C6I2 (SDHF2_MOUSE) findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- Function, matrix location and family statements come from HAMAP rule MF_03057 (ECO:0000255), a curated UniRule family assignment. They are family-level, not mouse experimental evidence. - id: file:mouse/Sdhaf2__Q8C6I2/Sdhaf2__Q8C6I2-notes.md title: mouse/Sdhaf2__Q8C6I2/Sdhaf2__Q8C6I2-notes.md findings: [] core_functions: - description: >- Non-catalytic chaperone and assembly factor for succinate dehydrogenase (respiratory complex II). It binds the flavoprotein subunit SDHA in the mitochondrial matrix and, with a dicarboxylate, orients the SDHA flavin and capping domains so that FAD can be covalently attached. Flavinylated SDHA is required for complex II to assemble into an active enzyme. For mouse, the chaperone mechanism and flavinylation are inferred from the PTHR12469:SF2 subfamily (human SDHAF2 structure, yeast Sdh5 genetics). Mouse muscle and myocyte data support the complex II assembly role directly: mitochondrial Sdhaf2 levels track complex II assembly, and Sdhaf2 restores succinate-linked respiration. molecular_function: id: GO:0044183 label: protein folding chaperone directly_involved_in: - id: GO:0018293 label: protein-FAD linkage - id: GO:0034553 label: mitochondrial respiratory chain complex II assembly locations: - id: GO:0005759 label: mitochondrial matrix supported_by: - reference_id: PMID:32887801 supporting_text: >- works in synergy with SDHAF2 to properly orient the flavin and capping domains of SDHA - reference_id: PMID:19628817 supporting_text: >- Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination (incorporation of the flavin adenine dinucleotide cofactor) - reference_id: PMID:38569044 supporting_text: Restoration of Sdhaf2 normalized complex II suggested_questions: - question: >- Does the cytosolic pool of Sdhaf2 seen in mouse myotubes have a function, or is it only precursor waiting for import? Is the reported Drp1-Sdhaf2 interaction direct on the outer membrane, given that Sdhaf2 has a canonical matrix-targeting presequence? - question: >- Does the EMT/Wnt phenotype of Sdhaf2-knockout mouse lung follow from loss of complex II and succinate accumulation (as in other SDHx-deficient tissues), or from a separate Sdhaf2-GSK-3beta interaction? - question: >- Is the SDH-independent complex IV assembly role reported for human SDHAF2 conserved in mouse tissues? suggested_experiments: - description: >- Measure covalent SDHA flavinylation (FAD fluorescence of SDHA on SDS-PAGE) and complex II assembly by BN-PAGE in tissues from a conditional Sdhaf2-knockout mouse. This would test directly, in mouse, the flavinylation role currently inferred from orthologs. experiment_type: genetic perturbation with biochemical readout - description: >- Compare wild-type and SDHA-binding-deficient Sdhaf2 (the residue equivalent to human G78R) for their ability to rescue lung EMT markers in Sdhaf2-null cells. This would separate complex II-dependent effects from the reported GSK-3beta signalling role. experiment_type: separation-of-function rescue