UQCC2 (ubiquinol-cytochrome c reductase complex assembly factor 2; also known as MNF1, M19 and C6orf125) is a small (126 aa) nuclear-encoded mitochondrial assembly factor for respiratory chain Complex III (cytochrome bc1 / ubiquinol-cytochrome c oxidoreductase). It is imported into mitochondria via an N-terminal transit peptide and localises predominantly to the mitochondrial inner membrane, with additional pools reported in the matrix and mitochondrial nucleoid. UQCC2 is the human ortholog of Saccharomyces cerevisiae Cbp6p and partners with UQCC1 (the ortholog of Cbp3p); the two proteins are mutually required for each other's stability. The UQCC1-UQCC2 module activates translation of, and stabilises, the mitochondrially-encoded cytochrome b subunit (MT-CYB), delivering it to an early Complex III assembly intermediate. UQCC2 is non-catalytic. Loss-of-function causes mitochondrial complex III deficiency, nuclear type 7 (MC3DN7), presenting with severe intrauterine growth retardation, neonatal lactic acidosis and renal tubular dysfunction.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005759 mitochondrial matrix | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assertion that UQCC2 acts in the mitochondrial matrix. Consistent with experimental localisation of the human ortholog: protease-protection experiments sublocalise M19/UQCC2 to the matrix space, and UniProt lists mitochondrion matrix as a primary location. Reason: Matrix localisation is directly supported by protease-protection data for human UQCC2 and is consistent with the UniProt SUBCELLULAR LOCATION. A soluble/peripheral matrix pool is compatible with the predominant inner-membrane association of the CIII assembly module. Supporting Evidence: PMID:19643811 protease-protection experiment showed it to be sublocalized in the matrix space |
| GO:0034551 mitochondrial respiratory chain complex III assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assertion of the core function: UQCC2 is a Complex III assembly factor. This is the central, experimentally established role of the gene and matches the mirrored IDA annotation from PMID:24385928. Reason: This is the core biological process for UQCC2, established both by orthology to the yeast CIII assembly factor Cbp6p and by direct functional studies in human cells showing UQCC2 loss causes Complex III deficiency. Supporting Evidence: PMID:24385928 role of UQCC2 as a complex III assembly factor that cooperates with UQCC1 |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic UniProt SubCell mapping to mitochondrion. Correct and well supported by multiple experimental studies; the most general and least controversial localisation. Reason: Mitochondrial localisation is confirmed by mass spectrometry, immunofluorescence (HPA), and targeted experimental studies; this IEA is fully corroborated. Supporting Evidence: PMID:19643811 Human M19 (hM19) is present in mitochondria |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic UniProt SubCell mapping to the mitochondrial inner membrane. UniProt notes UQCC2 is predominantly expressed in the inner membrane, consistent with its role in membrane insertion of nascent cytochrome b during CIII assembly. Reason: The inner membrane is the predominant reported location and is where the UQCC1-UQCC2 module operates on the membrane-integral MT-CYB; supported by the UniProt record. Supporting Evidence: file:human/UQCC2/UQCC2-uniprot.txt Predominantly expressed in the mitochondrial inner membrane. |
| GO:0005758 mitochondrial intermembrane space | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic UniProt SubCell mapping to the intermembrane space. In UniProt this location carries only by-similarity (ECO:0000250) evidence; it is plausible but less strongly supported than the matrix/inner-membrane pools. Reason: Listed as a UniProt subcellular location (by similarity). Not contradicted by experimental data; retained as a peripheral/minor localisation rather than a core role. Supporting Evidence: file:human/UQCC2/UQCC2-uniprot.txt Mitochondrion intermembrane space {ECO:0000250}. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic UniProt SubCell mapping to the matrix. Duplicates the IBA/IDA-supported matrix localisation (protease-protection of human UQCC2 places it in the matrix space). Reason: Matrix localisation is experimentally supported for human UQCC2; this IEA duplicate is consistent and acceptable. Supporting Evidence: PMID:19643811 protease-protection experiment showed it to be sublocalized in the matrix space |
| GO:0042645 mitochondrial nucleoid | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic UniProt SubCell mapping to the mitochondrial nucleoid. Supported by the original M19 characterisation showing co-localisation with mtDNA and co-fractionation with known nucleoid components. Reason: Nucleoid association is experimentally documented (PMID:19643811). Although later work showed nucleoids are not disturbed in UQCC2-deficient patient cells (arguing the nucleoid link is not the core function), the localisation itself is valid. Supporting Evidence: PMID:19643811 co-localized with signals arising from mitochondrial DNA (mtDNA), suggesting the inclusion of M19 in the mtDNA-protein complex (mitochondrial nucleoids) |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: High-throughput binary interactome (HuRI) IPI. The reported preys (CDKN2D, EXOC8, GNG13, MKRN3, MRFAP1, NRDE2, SNAP25, TRAPPC2, TXN2, ZNF765, plus UQCC1) are largely non-mitochondrial and are not connected to Complex III assembly; these are uninformative and likely include screen artifacts. Reason: Bare `protein binding` conveys no functional information, and the bulk of the preys from this systematic screen are non-mitochondrial proteins with no known relationship to UQCC2 biology. Per curation policy this bare-protein-binding IPI is marked as over-annotated rather than removed. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | ACCEPT | Summary: Proteome-scale interaction network (BioPlex) IPI with UQCC1 (Q9NVA1). This recovers the biologically meaningful partner of UQCC2, but the GO term itself (`protein binding`) is uninformative. Reason: The recorded partner is UQCC1, the genuine functional binding partner, so the evidence is sound; however `protein binding` is not a core molecular function. Kept as supporting interaction evidence rather than used in core_functions. Supporting Evidence: PMID:24385928 revealed efficient co-isolation of UQCC1 |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | ACCEPT | Summary: Multimodal cell-map / interaction-network IPI with UQCC1 (Q9NVA1), again recovering the correct functional partner. `protein binding` remains uninformative as a term. Reason: The prey is UQCC1, the established partner; the interaction is real and consistent with the UQCC1-UQCC2 module. Retained as interaction evidence, not as a core molecular function. Supporting Evidence: PMID:24385928 revealed efficient co-isolation of UQCC1 |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence localisation (Human Protein Atlas) to mitochondrion. Consistent with all other localisation evidence. Reason: Independent IDA (imaging) confirmation of mitochondrial localisation; fully consistent with the mass-spectrometry and targeted studies. Supporting Evidence: PMID:19643811 Human M19 (hM19) is present in mitochondria |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput mitochondrial proteome study assigns UQCC2 to the mitochondrion. Corroborates the curated mitochondrial localisation. Reason: Consistent high-throughput confirmation of mitochondrial localisation; no conflict with other evidence. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics |
| GO:0005515 protein binding | IPI PMID:24385928 Mutations in the UQCC1-interacting protein, UQCC2, cause hum... | ACCEPT | Summary: IPI with UQCC1 (Q9NVA1) from the primary functional paper. Co-affinity purification (UQCC2-TAP and reciprocal UQCC1-TAP) demonstrates a direct, functionally central interaction between UQCC2 and UQCC1. Reason: This is the biologically meaningful, experimentally validated interaction underlying the UQCC1-UQCC2 assembly module. Although the term is bare `protein binding`, the partner (UQCC1) is the correct, core functional partner, so the annotation is accepted as valid supporting evidence. Supporting Evidence: PMID:24385928 revealed efficient co-isolation of UQCC1 PMID:24385928 UQCC2 interacts with UQCC1 |
| GO:0034551 mitochondrial respiratory chain complex III assembly | IDA PMID:24385928 Mutations in the UQCC1-interacting protein, UQCC2, cause hum... | ACCEPT | Summary: Direct experimental evidence (patient fibroblasts, lentiviral rescue, siRNA knockdown, BN-PAGE) that UQCC2 is required for assembly of Complex III. This is the core function of the gene. Reason: Loss of UQCC2 causes severe Complex III deficiency that is rescued by re-expression of wild-type UQCC2, establishing a direct requirement in CIII assembly. Core BP. Supporting Evidence: PMID:24385928 role of UQCC2 as a complex III assembly factor that cooperates with UQCC1 PMID:24385928 UQCC1 and UQCC2 are critical factors required for the expression of cytochrome b and complex III biogenesis |
| GO:0070131 positive regulation of mitochondrial translation | IDA PMID:24385928 Mutations in the UQCC1-interacting protein, UQCC2, cause hum... | ACCEPT | Summary: UQCC2 (with UQCC1) activates translation of, and stabilises, mtDNA-encoded cytochrome b (MT-CYB). Patient cells show a specific defect in cytochrome b protein synthesis/stability despite normal MT-CYB mRNA levels, consistent with a positive role in mitochondrial translation of this transcript. Reason: The UQCC1-UQCC2 module functions analogously to the yeast Cbp3p-Cbp6p translational activators of cytochrome b; the human data (specific loss of cytochrome b protein with unaffected mRNA) support a positive-regulation-of-mitochondrial-translation role for the MT-CYB transcript. Supporting Evidence: PMID:24385928 activate translation of mtDNA-encoded cytochrome b, bind and stabilize the newly synthesized protein PMID:24385928 MT-CYB mRNA levels were unaffected in patient cells PMID:24385928 a striking and specific defect in cytochrome b protein levels was observed |
| GO:0002082 regulation of oxidative phosphorylation | IMP PMID:22363741 M19 modulates skeletal muscle differentiation and insulin se... | ACCEPT | Summary: RNAi and over-expression of M19/UQCC2 modulate mitochondrial oxygen consumption and ATP production, indicating regulation of respiratory chain / oxidative phosphorylation activity. This is a downstream consequence of its role in Complex III assembly. Reason: Perturbing UQCC2 changes OXPHOS output (O2 consumption, ATP production), which is consistent with regulation of oxidative phosphorylation. This effect is mechanistically downstream of the core CIII-assembly function. Supporting Evidence: PMID:22363741 M19 modulates mitochondrial oxygen consumption and ATP production |
| GO:0005739 mitochondrion | IDA PMID:22363741 M19 modulates skeletal muscle differentiation and insulin se... | ACCEPT | Summary: Direct localisation of M19/UQCC2 to mitochondria, mediated by an N-terminal 13-residue targeting sequence. Consistent with all other localisation evidence. Reason: Independent IDA confirmation of mitochondrial localisation and identification of the mitochondrial targeting signal. Supporting Evidence: PMID:22363741 13-long amino acid sequence located at the N-terminus of M19 that targets the protein to mitochondria |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer (from mouse ortholog Q9CQY6) of inner-membrane localisation. Consistent with UniProt noting UQCC2 is predominantly expressed in the inner membrane. Reason: Inner membrane is the predominant reported location; the ISS transfer from the mouse ortholog is concordant with the human UniProt record. Supporting Evidence: file:human/UQCC2/UQCC2-uniprot.txt Predominantly expressed in the mitochondrial inner membrane. |
| GO:0005758 mitochondrial intermembrane space | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer (from mouse ortholog Q9CQY6) of intermembrane-space localisation. Duplicates the IEA IMS annotation; a plausible peripheral pool. Reason: Concordant with the UniProt subcellular location list (by similarity). Retained as a minor/peripheral localisation, not a core role. Supporting Evidence: file:human/UQCC2/UQCC2-uniprot.txt Mitochondrion intermembrane space {ECO:0000250}. |
| GO:0005759 mitochondrial matrix | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer (from mouse ortholog Q9CQY6) of matrix localisation. Concordant with the protease-protection evidence placing human UQCC2 in the matrix space. Reason: Matrix localisation is experimentally supported for the human protein and by orthology; the ISS transfer is consistent. Supporting Evidence: PMID:19643811 protease-protection experiment showed it to be sublocalized in the matrix space |
| GO:0050796 regulation of insulin secretion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer of a physiological role in insulin secretion. In INS-1 pancreatic beta-cells M19/UQCC2 plays a permissive role in insulin secretion under basal glucose conditions, an indirect consequence of its modulation of respiratory chain activity. Reason: This is a downstream, tissue-specific physiological effect that operates through altered OXPHOS/ATP output rather than a direct molecular role of UQCC2. Retained as a non-core annotation. Supporting Evidence: PMID:22363741 plays a permissive role on insulin secretion under basal glucose conditions in INS-1 pancreatic |
| GO:2001014 regulation of skeletal muscle cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer of a role in muscle differentiation. In C2C12 myogenic cells M19/UQCC2 acts on late muscle differentiation, an indirect effect of its modulation of mitochondrial ATP production. Reason: A downstream, tissue-specific developmental effect mediated by altered respiratory chain activity, not a direct molecular function of UQCC2. Retained as non-core. Supporting Evidence: PMID:22363741 acts on late muscle differentiation in myogenic C2C12 cells |
| GO:0042645 mitochondrial nucleoid | IDA PMID:19643811 Association of a novel mitochondrial protein M19 with mitoch... | ACCEPT | Summary: Direct experimental evidence: tagged M19/UQCC2 co-localises with mtDNA and co-fractionates with known nucleoid components, placing it in the mitochondrial nucleoid. This is the original characterisation of the protein. Reason: Well-supported IDA nucleoid association. Note that this is a localisation rather than the core CIII-assembly function, and later work found nucleoids are undisturbed in UQCC2-deficient patient cells; nonetheless the localisation is valid. Supporting Evidence: PMID:19643811 co-localized with signals arising from mitochondrial DNA (mtDNA), suggesting the inclusion of M19 in the mtDNA-protein complex (mitochondrial nucleoids) |
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Download this section (compressed HTML)Q: Does UQCC2 have any role beyond MT-CYB translation/stabilisation, and is its nucleoid association functionally meaningful or merely a consequence of its inner-membrane/matrix localisation near mtDNA?
Q: Which residues of UQCC2 mediate the UQCC1 interaction and MT-CYB stabilisation, and could a more specific molecular function term (e.g. a translational-activator or chaperone activity) be justified beyond `protein binding`?
Experiment: Structural/crosslinking analysis of the human UQCC1-UQCC2 (and COMA/COMB/COMC) complexes bound to nascent MT-CYB to define UQCC2's precise molecular role and any specific activity.
Experiment: Ribosome profiling / mitochondrial translation assays in UQCC2-null versus rescued cells to quantify the MT-CYB translational-activation defect independently of protein stability.
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