UQCRH (ubiquinol-cytochrome c reductase hinge protein; cytochrome b-c1 complex subunit 6, also called Complex III subunit 6/VIII or the "hinge" protein) is a small (91-residue precursor; 14-91 mature) nuclear-encoded structural subunit of the mitochondrial respiratory chain Complex III (cytochrome bc1 / ubiquinol-cytochrome c oxidoreductase). It is imported into mitochondria via an unusually acidic N-terminal transit peptide and resides as a peripheral membrane protein on the intermembrane-space side of the mitochondrial inner membrane. UQCRH is one of the low-molecular-weight, non-catalytic subunits of the obligate CIII dimer; the catalytic redox centres are carried by cytochrome b (MT-CYB), cytochrome c1 (CYC1) and the Rieske iron-sulfur protein (UQCRFS1). The acidic hinge protein forms the docking interface that "hinges" cytochrome c to cytochrome c1, and is required for correct interaction and electron transfer between cytochrome c1 and soluble cytochrome c. Loss of UQCRH destabilizes the assembled holoenzyme, reduces Complex III catalytic activity, and causes mitochondrial complex III deficiency (nuclear type 11), presenting with lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy. Its overall role is therefore structural/assembly and electron-transfer facilitation within Complex III during aerobic respiration and oxidative phosphorylation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0045275 respiratory chain complex III | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically-inferred assignment of UQCRH as a component of respiratory chain Complex III (cytochrome bc1). This is the correct, specific complex for this subunit and is strongly supported by structural, biochemical and disease evidence. Reason: UQCRH is a bona fide low-molecular-weight subunit of the 11-subunit cytochrome b-c1 complex (CIII); this is confirmed experimentally by cryo-EM structure and by the CIII deficiency caused by its loss. GO:0045275 is the current, correct term (the legacy GO:0005750 is obsolete). Supporting Evidence: PMID:34750991 encodes a structural complex III (CIII) subunit file:human/UQCRH/UQCRH-uniprot.txt 6 low-molecular weight protein subunits UQCRH/QCR6, UQCRB/QCR7, UQCRQ/QCR8, |
| GO:0006122 mitochondrial electron transport, ubiquinol to cytochrome c | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically-inferred involvement in the Complex III reaction that transfers electrons from ubiquinol to cytochrome c. This is the core biological process of Complex III and the most specific correct BP term for this subunit. Reason: As a subunit of CIII, UQCRH participates in the ubiquinol-to-cytochrome-c electron transport reaction; the hinge protein specifically mediates the cytochrome c1-cytochrome c docking/electron-transfer step. This is the representative core BP. Supporting Evidence: PMID:34750991 CIII transports electrons from ubiquinol to cytochrome c and translocates protons across the inner mitochondrial membrane PMID:2826252 Mitochondrial hinge protein is a subunit of ubiquinol-cytochrome-c reductase in |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Subcellular-location mapping to the mitochondrial inner membrane, consistent with UniProt annotation of UQCRH as a peripheral inner-membrane protein on the intermembrane side. Reason: Correct and specific localization for a CIII subunit; independently supported by experimental IDA (PMID:28844695, ComplexPortal) and by UniProt subcellular location. Supporting Evidence: file:human/UQCRH/UQCRH-uniprot.txt Mitochondrion inner membrane |
| GO:0006122 mitochondrial electron transport, ubiquinol to cytochrome c | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping (IPR003422, Cyt_b-c1_6 / hinge domain) to the CIII electron transport process. Duplicates the IBA core BP term via an orthogonal, domain-based line of evidence. Reason: The hinge-domain signature correctly implies participation in ubiquinol-to-cytochrome-c electron transport; consistent with the IBA annotation. Duplicate of the core BP is acceptable. Supporting Evidence: PMID:2826252 Mitochondrial hinge protein is a subunit of ubiquinol-cytochrome-c reductase in |
| GO:0016020 membrane | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Generic ARBA electronic annotation to "membrane". This is a high-level parent of the specific and experimentally supported mitochondrial inner membrane term. Reason: Not wrong, but uninformatively general: the specific location (GO:0005743 mitochondrial inner membrane) is well established, so the bare "membrane" term adds no information and should not be treated as a core localization. Supporting Evidence: file:human/UQCRH/UQCRH-uniprot.txt Mitochondrion inner membrane |
| GO:0098803 respiratory chain complex | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic annotation placing UQCRH in a (generic) respiratory chain complex. Correct but is the parent of the specific term respiratory chain complex III (GO:0045275). Reason: Accurate but less specific than GO:0045275, which captures the exact complex. Retain as a valid but non-core (redundant-parent) annotation. Supporting Evidence: file:human/UQCRH/UQCRH-uniprot.txt 6 low-molecular weight protein subunits UQCRH/QCR6, UQCRB/QCR7, UQCRQ/QCR8, |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Logically-inferred BP from the quinol-cytochrome-c reductase activity term: Complex III couples electron transfer to translocation of protons across the inner membrane in the Q cycle. Reason: The proton translocation is a genuine, complex-level consequence of the CIII reaction, but UQCRH is a non-catalytic hinge subunit that does not itself conduct protons; this is a context/complex-level role rather than the subunit's core function. Keep as non-core. Supporting Evidence: PMID:34750991 CIII transports electrons from ubiquinol to cytochrome c and translocates protons across the inner mitochondrial membrane Reactome:R-HSA-164651 complex III transfers electrons from ubiquinol to cytochrome c, linking this process to translocation of protons across the membrane |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a proteome-scale binary interactome (Y2H) screen. The reported partners (e.g. ARL8A, RNF24, ENTREP3) are not Complex III subunits. Reason: "Protein binding" is uninformative and does not describe a molecular function; the high-throughput binary interactors are cytosolic/endosomal proteins with no obvious physiological relationship to a mitochondrial inner-membrane CIII subunit, so this is likely a non-specific/spurious interaction. Retained (not removed, per policy for experimental IPIs) but flagged as over-annotation. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a reference binary-interactome (HuRI, Y2H) map. Partners (e.g. NDFIP1, NDFIP2, PRRG1) are not Complex III components. Reason: Same rationale as the other protein-binding IPI: uninformative MF term and non-CIII high-throughput binary partners with no established physiological role for this inner-membrane subunit. Retained but flagged as over-annotation. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: Direct assay (ComplexPortal, from cryo-EM of the human respiratory megacomplex) localizing UQCRH to the mitochondrial inner membrane as part of Complex III. Reason: Experimental (IDA) localization to the correct, specific compartment; the cryo-EM structure resolves UQCRH within the membrane-embedded CIII dimer. Core localization. Supporting Evidence: PMID:28844695 are positioned to accept electrons on the surface of the c1 state CIII dimer |
| GO:0006122 mitochondrial electron transport, ubiquinol to cytochrome c | NAS PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: ComplexPortal (NAS) involvement of UQCRH in the ubiquinol-to-cytochrome-c electron transport reaction of Complex III. Reason: Correct core BP for a CIII subunit; the megacomplex structure shows cytochrome c docking on the c1-state CIII dimer, the reaction in which UQCRH's hinge role operates. Duplicate of the core BP term. Supporting Evidence: PMID:28844695 are positioned to accept electrons on the surface of the c1 state CIII dimer |
| GO:0045275 respiratory chain complex III | IPI PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: ComplexPortal (IPI) assignment of UQCRH as a part of respiratory chain Complex III, based on the cryo-EM megacomplex structure. Reason: Experimentally supported membership of the correct, specific complex; consistent with the IBA annotation and with UniProt's 11-subunit CIII composition. Core CC. Supporting Evidence: file:human/UQCRH/UQCRH-uniprot.txt 6 low-molecular weight protein subunits UQCRH/QCR6, UQCRB/QCR7, UQCRQ/QCR8, |
| GO:0045333 cellular respiration | NAS PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | KEEP AS NON CORE | Summary: ComplexPortal (NAS) involvement in cellular respiration, reflecting Complex III's role in the respiratory electron transport chain. Reason: Correct high-level BP context, but broader than the specific core term GO:0006122; keep as valid non-core. Supporting Evidence: PMID:34750991 CIII transports electrons from ubiquinol to cytochrome c and translocates protons across the inner mitochondrial membrane |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput mitochondrial proteome localization to the mitochondrion. Correct but a generic parent of the specific inner-membrane localization. Reason: Accurate compartment but less specific than GO:0005743 (mitochondrial inner membrane), which is experimentally established; keep as valid non-core. Supporting Evidence: file:human/UQCRH/UQCRH-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer (from ortholog UniProtKB:P00127) of the mitochondrial inner membrane localization. Reason: Correct, specific localization; consistent with experimental IDA and UniProt. Duplicate of the core CC term via orthology. Supporting Evidence: file:human/UQCRH/UQCRH-uniprot.txt Mitochondrion inner membrane |
| GO:0008121 quinol-cytochrome-c reductase activity | IMP PMID:34750991 Characterising a homozygous two-exon deletion in UQCRH: comp... | MARK AS OVER ANNOTATED | Summary: IMP based on the homozygous two-exon UQCRH deletion, which reduces Complex III (quinol-cytochrome-c reductase) activity to ~50-60% of control. This is the whole-complex catalytic activity; UQCRH is a non-catalytic structural/hinge subunit, so the loss of activity reflects a structural/assembly requirement, not catalysis by UQCRH itself. Reason: The catalytic centres of CIII are carried by cytochrome b (MT-CYB), cytochrome c1 (CYC1) and the Rieske protein (UQCRFS1); UQCRH is explicitly a structural subunit whose precise function "remains to be fully elucidated" and which "hinges" cytochrome c to c1. The IMP phenotype (loss of UQCRH lowers CIII activity) is fully explained by a structural/assembly role, and does not demonstrate that UQCRH itself enables quinol-cytochrome-c reductase catalysis. Assigning the complex's catalytic MF to this non-catalytic subunit is an over-annotation; the subunit's MF is better captured as structural molecule activity (GO:0005198) contributing to the complex activity. Retained (experimental) but flagged. Supporting Evidence: PMID:34750991 confirmed a specific decrease of CIII activity to approximately 60% compared to control cell lines PMID:34750991 remains to be fully elucidated PMID:2826252 and 'hinges' cytochrome c with cytochrome c1 |
| GO:0005739 mitochondrion | HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated... | KEEP AS NON CORE | Summary: High-throughput direct assay (mitochondrial phosphoproteome of human muscle) localizing UQCRH to the mitochondrion. Reason: Correct but generic parent of the specific inner-membrane localization; keep as valid non-core. Supporting Evidence: file:human/UQCRH/UQCRH-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-164651 | ACCEPT | Summary: Reactome (TAS) localization to the mitochondrial inner membrane, from the pathway describing electron transfer from ubiquinol to cytochrome c by Complex III. Reason: Correct, specific localization consistent with experimental and UniProt evidence. Duplicate of the core CC term. Supporting Evidence: Reactome:R-HSA-164651 complex III transfers electrons from ubiquinol to cytochrome c, linking this process to translocation of protons across the membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9906017 | ACCEPT | Summary: Reactome (TAS) inner-membrane localization from the CIII assembly pathway (UQCRFS1 processing). Correct localization for the assembled complex context. Reason: Correct, specific localization; consistent with all other lines of evidence. Duplicate of the core CC term. Supporting Evidence: file:human/UQCRH/UQCRH-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9906042 | ACCEPT | Summary: Reactome (TAS) inner-membrane localization from the CIII assembly pathway (TTC19 clearance of UQCRFS1 fragments). Correct localization for the complex context. Reason: Correct, specific localization; consistent with all other evidence. Duplicate of the core CC term. Supporting Evidence: file:human/UQCRH/UQCRH-uniprot.txt Mitochondrion inner membrane |
| GO:0006119 oxidative phosphorylation | TAS PMID:2826252 An extremely acidic amino-terminal presequence of the precur... | KEEP AS NON CORE | Summary: TAS involvement in oxidative phosphorylation, reflecting Complex III's place in the OXPHOS electron transport chain that drives ATP synthesis. Reason: Correct high-level BP context but broader than the specific core term GO:0006122; keep as valid non-core. Supporting Evidence: PMID:34750991 CIII transports electrons from ubiquinol to cytochrome c and translocates protons across the inner mitochondrial membrane |
| GO:0008121 quinol-cytochrome-c reductase activity | TAS PMID:2826252 An extremely acidic amino-terminal presequence of the precur... | MARK AS OVER ANNOTATED | Summary: TAS (PINC) assignment of quinol-cytochrome-c reductase activity, i.e. the whole Complex III catalytic activity, to UQCRH. UQCRH is the non-catalytic hinge subunit. Reason: As with the IMP annotation to the same term, this attributes the complex's catalytic MF to a structural, non-catalytic subunit. The 1987 paper itself describes UQCRH only as a subunit that "hinges" cytochrome c to c1, not as the catalytic entity. Better represented as structural molecule activity contributing to the complex activity; flagged as over-annotation. Supporting Evidence: PMID:2826252 and 'hinges' cytochrome c with cytochrome c1 |
| GO:0009060 aerobic respiration | TAS PMID:2826252 An extremely acidic amino-terminal presequence of the precur... | KEEP AS NON CORE | Summary: TAS involvement in aerobic respiration, reflecting the role of the ubiquinol-cytochrome-c reductase in the aerobic respiratory chain. Reason: Correct high-level BP context but broader than the specific core term GO:0006122; keep as valid non-core. Supporting Evidence: PMID:2826252 Mitochondrial hinge protein is a subunit of ubiquinol-cytochrome-c reductase in |
| GO:0098803 respiratory chain complex | TAS PMID:2826252 An extremely acidic amino-terminal presequence of the precur... | KEEP AS NON CORE | Summary: TAS assignment of UQCRH to a respiratory chain complex. Correct but generic parent of the specific respiratory chain complex III term. Reason: Accurate but less specific than GO:0045275 (respiratory chain complex III); keep as valid non-core. Supporting Evidence: PMID:2826252 Mitochondrial hinge protein is a subunit of ubiquinol-cytochrome-c reductase in |
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Download this section (compressed HTML)Q: Does UQCRH have any role beyond CIII assembly/structure and cytochrome c docking (e.g. a regulatory or supercomplex-organizing role), given the altered supercomplex distribution observed upon its loss?
Experiment: Structure-guided mutagenesis of the acidic N-terminal region and the cytochrome c docking surface of UQCRH to quantify effects on cytochrome c1-cytochrome c electron transfer versus overall CIII assembly and stability.
Hypothesis: The acidic hinge region of UQCRH is specifically required for cytochrome c docking and c1-to-c electron transfer, separable from its contribution to CIII holoenzyme assembly/stability.
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