ETFDH

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005743 mitochondrial inner membrane	IBA GO_REF:0000033	ACCEPT	Summary: ETF-QO is an integral (monotopic) protein of the mitochondrial inner membrane, where it acts. This is the core subcellular location and is directly supported by experiment. Reason: Direct experimental evidence and structural data localize ETF-QO to the inner mitochondrial membrane; the IBA annotation is at the correct level of specificity and matches the human IDA below (PMID:8306995). Supporting Evidence: PMID:8306995 Electron-transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) in the inner mitochondrial membrane accepts electrons from electron-transfer flavoprotein PMID:17050691 Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) is a 4Fe4S flavoprotein located in the inner mitochondrial membrane.
GO:0004174 electron-transferring-flavoprotein dehydrogenase activity	IBA GO_REF:0000033	ACCEPT	Summary: This is the defining molecular function of ETFDH (EC 1.5.5.1): oxidation of reduced ETF with reduction of ubiquinone. Strongly supported by direct human enzymology. Reason: The IBA annotation matches the multiple human IDA annotations (PMID:12049629, PMID:8306995) and the UniProt catalytic activity. It is the core function of the gene. Supporting Evidence: PMID:12049629 Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) is an iron-sulphur flavoprotein and a component of an electron-transfer system that links 10 different mitochondrial flavoprotein dehydrogenases to the mitochondrial bc1 complex via electron transfer flavoprotein (ETF) and ubiquinone.
GO:0022900 electron transport chain	IBA GO_REF:0000033	ACCEPT	Summary: ETF-QO participates in mitochondrial electron transport by reducing the ubiquinone pool, feeding electrons from primary flavoprotein dehydrogenases into the respiratory chain. Reason: Correct and appropriately general biological process; concordant with the human IDA annotations to this term and with the Reactome respiratory-electron-transport annotation. Supporting Evidence: PMID:18037314 Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) is a membrane-bound electron transfer protein that links primary flavoprotein dehydrogenases with the main respiratory chain.
GO:0004174 electron-transferring-flavoprotein dehydrogenase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment of the core catalytic activity via InterPro/RHEA/EC mapping (EC 1.5.5.1, RHEA:24052). Consistent with experimental data. Reason: The IEA maps IPR040156 (ETF-QO) and EC 1.5.5.1 to GO:0004174, the experimentally established function; correct and specific. Supporting Evidence: PMID:12049629 a component of an electron-transfer system that links 10 different mitochondrial flavoprotein dehydrogenases to the mitochondrial bc1 complex
GO:0005739 mitochondrion	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Broad mitochondrial localization (ARBA electronic). Correct but less specific than the experimentally supported inner-membrane location. Reason: Accurate but a general parent of the inner-membrane annotation; retained as a broader, non-core localization statement. Supporting Evidence: PMID:8306995 which targets the protein to mitochondria
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000044	ACCEPT	Summary: Inner-membrane localization from UniProt Subcellular Location mapping (SL-0168). Matches the experimental IDA. Reason: Correct and specific; equivalent to the experimentally supported location. Supporting Evidence: PMID:17050691 ETF-QO is a monotopic integral membrane protein.
GO:0022900 electron transport chain	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic assignment of electron transport chain involvement; matches the experimentally supported process. Reason: Consistent with IBA and human IDA annotations to the same term; correct. Supporting Evidence: PMID:18037314 a membrane-bound electron transfer protein that links primary flavoprotein dehydrogenases with the main respiratory chain
GO:0051536 iron-sulfur cluster binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: ETF-QO binds one [4Fe-4S] cluster; this InterPro-derived term is the broader parent of the more specific IDA-supported GO:0051539. Reason: Correct but less specific than 4 iron, 4 sulfur cluster binding (GO:0051539); retained as a broader cofactor-binding statement. Supporting Evidence: PMID:8306995 The two redox centers in the protein, FAD and a [4Fe4S]+2,+1 cluster, are present in a 64-kDa monomer.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Seven high-throughput yeast two-hybrid interactions (HuRI) with keratin-associated proteins, transcription factors (OTX1, GSC2, ZNF581) and other proteins (MYH7B, TRIM69, KRTAP11-1/13-2) that share no compartment or pathway with this mitochondrial inner-membrane oxidoreductase. The bare "protein binding" term is also uninformative. Reason: These are large-scale binary-interactome (Y2H) hits from a reference interactome map with no functional context; the partners are cytoplasmic/nuclear and biologically implausible for an inner-membrane enzyme, and the generic term conveys no molecular function. Marked as over-annotated per policy rather than removed. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome.
GO:0006979 response to oxidative stress	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ortholog-transferred (Ensembl Compara, from mouse Etfdh) association with oxidative-stress response. This is a downstream/phenotypic consequence rather than a direct molecular function of the electron-transfer reaction. Reason: The term is electronically transferred from the mouse ortholog and reflects a secondary phenotype (impaired electron flux increases electron leak/ROS) rather than a core activity of ETF-QO; retained but flagged as over-annotated. Supporting Evidence: GO_REF:0000107 Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO:0022904 respiratory electron transport chain	TAS Reactome:R-HSA-611105	ACCEPT	Summary: Reactome places ETFDH in respiratory electron transport, reducing coenzyme Q; a correct, specific process for this enzyme. Reason: Traceable author statement (Reactome) consistent with the enzyme's role of feeding electrons into the ubiquinone pool of the respiratory chain. Supporting Evidence: PMID:17050691 It catalyzes ubiquinone (UQ) reduction by ETF, linking oxidation of fatty acids and some amino acids to the mitochondrial respiratory chain.
GO:0004174 electron-transferring-flavoprotein dehydrogenase activity	TAS Reactome:R-HSA-169270	ACCEPT	Summary: Reactome reaction (ETFDH oxidises reduced ETF, reduces CoQ to CoQH2) assigning the core catalytic activity. Correct. Reason: Concordant with experimental IDA and the enzyme's EC 1.5.5.1 catalytic activity. Supporting Evidence: PMID:12049629 The steady-state kinetic constants of human ETF-QO were determined with ubiquinone homologues, a ubiquinone analogue, and with human wild-type ETF
GO:0005739 mitochondrion	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: Immunofluorescence (HPA) localizes ETFDH to mitochondria. Correct but a broad parent of the specific inner-membrane location. Reason: Accurate general localization; less specific than the inner-membrane annotation, so kept as a non-core broader term. Supporting Evidence: PMID:8306995 which targets the protein to mitochondria
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	KEEP AS NON CORE	Summary: High-throughput mitochondrial proteomics identifies ETFDH as a mitochondrial protein. Correct but broad. Reason: Supports mitochondrial localization at low specificity; consistent with the experimentally established inner-membrane location, kept as non-core. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-169270	ACCEPT	Summary: Reactome asserts inner-membrane localization for the ETFDH reaction; matches experimental data. Reason: Correct, specific location concordant with the IDA and structural evidence. Supporting Evidence: PMID:17050691 Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) is a 4Fe4S flavoprotein located in the inner mitochondrial membrane.
GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase	IMP PMID:17412732 The myopathic form of coenzyme Q10 deficiency is caused by m...	ACCEPT	Summary: ETFDH mutations cause multiple acyl-CoA dehydrogenase deficiency with impaired fatty-acid beta-oxidation flux; ETF-QO is the electron acceptor for the acyl-CoA dehydrogenation step, so its loss blocks beta-oxidation. Reason: IMP evidence from patients with ETFDH mutations demonstrates the gene's required role in the acyl-CoA dehydrogenase branch of fatty-acid beta-oxidation (electron sink); this is the biologically central metabolic process that ETF-QO enables. Supporting Evidence: PMID:17412732 All of our patients carried autosomal recessive mutations in ETFDH, suggesting that ETFDH deficiency leads to a secondary CoQ10 deficiency. PMID:17050691 linking oxidation of fatty acids and some amino acids to the mitochondrial respiratory chain
GO:0004174 electron-transferring-flavoprotein dehydrogenase activity	IDA PMID:14640977 Alternative quinone substrates and inhibitors of human elect...	ACCEPT	Summary: Direct kinetic characterization of human ETF-QO catalyzing electron transfer from ETF to the ubiquinone pool. Core molecular function. Reason: Steady-state kinetics of purified human enzyme with ETF and ubiquinone substrates directly demonstrate the EC 1.5.5.1 activity. Supporting Evidence: PMID:14640977 a membrane-bound iron-sulphur flavoprotein that participates in an electron-transport pathway between eleven mitochondrial flavoprotein dehydrogenases and the ubiquinone pool
GO:0006979 response to oxidative stress	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: Sequence-similarity transfer from the mouse ortholog (Q921G7) of an oxidative-stress response role; a secondary/phenotypic association rather than a direct function of the electron-transfer reaction. Reason: As with the Ensembl IEA to the same term, this is transferred from mouse and reflects a downstream phenotype of impaired electron flux (increased ROS/electron leak), not a core molecular function; flagged as over-annotated. Supporting Evidence: GO_REF:0000024 Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO:0016491 oxidoreductase activity	IDA PMID:14640977 Alternative quinone substrates and inhibitors of human elect...	MARK AS OVER ANNOTATED	Summary: ETF-QO is an oxidoreductase, but this is the very general parent of the specific GO:0004174 activity established in the same study. Reason: Correct in essence but far too general given that the specific dehydrogenase activity (GO:0004174) is annotated with the same experimental evidence; retained as an over-annotation rather than as a core function. Supporting Evidence: PMID:14640977 The steady-state kinetic constants of human ETF-QO were determined with ubiquinone homologues and analogues
GO:0048038 quinone binding	IDA PMID:14640977 Alternative quinone substrates and inhibitors of human elect...	KEEP AS NON CORE	Summary: Fluorescence titrations demonstrate a single quinone-binding site per ETF-QO monomer. Correct; the parent of the more specific ubiquinone binding. Reason: Directly supported but broader than the specific ubiquinone binding annotation (GO:0048039); kept as a non-core broader term. Supporting Evidence: PMID:14640977 consistent with one ubiquinone-binding site per ETF-QO monomer
GO:0048039 ubiquinone binding	IDA PMID:14640977 Alternative quinone substrates and inhibitors of human elect...	ACCEPT	Summary: ETF-QO binds ubiquinone at a single site per monomer and reduces it; the physiological electron acceptor. Core function-related binding. Reason: Direct biophysical evidence (fluorescence titration, kinetics) for a specific ubiquinone-binding site; structurally corroborated. Specific and correct. Supporting Evidence: PMID:14640977 determined by fluorescence titrations of the protein with DBMIB and 6-(10-bromodecyl)ubiquinone, are consistent with one ubiquinone-binding site per ETF-QO monomer PMID:17050691 The UQ-binding pocket consists mainly of hydrophobic residues
GO:0051539 4 iron, 4 sulfur cluster binding	IDA PMID:18037314 Electron spin relaxation enhancement measurements of intersp...	ACCEPT	Summary: EPR/electron-spin-relaxation measurements confirm a single [4Fe-4S] cluster in human ETF-QO. Core cofactor binding. Reason: Direct spectroscopic evidence for one [4Fe-4S] cluster per monomer; specific and correct. Supporting Evidence: PMID:18037314 Human, porcine, and Rhodobacter sphaeroides ETF-QO each contain a single [4Fe-4S](2+,1+) cluster and one equivalent of FAD
GO:0004174 electron-transferring-flavoprotein dehydrogenase activity	IDA PMID:12049629 Expression of human electron transfer flavoprotein-ubiquinon...	ACCEPT	Summary: Kinetic and spectral characterization of recombinant human ETF-QO establishes the core EC 1.5.5.1 activity with ETF and ubiquinone substrates. Reason: Direct enzymology of the human protein; the defining molecular function. Supporting Evidence: PMID:12049629 The steady-state kinetic constants of human ETF-QO were determined with ubiquinone homologues, a ubiquinone analogue, and with human wild-type ETF
GO:0004174 electron-transferring-flavoprotein dehydrogenase activity	IDA PMID:8306995 Molecular cloning and expression of a cDNA encoding human el...	ACCEPT	Summary: Heterologously expressed human ETF-QO transfers electrons from ETF to ubiquinone, demonstrating the core catalytic activity with both cofactors correctly inserted. Reason: Direct functional demonstration of ETF-to-ubiquinone electron transfer by the human enzyme; defining molecular function. Supporting Evidence: PMID:8306995 The detergent-solubilized protein transfers electrons from ETF to the ubiquinone homolog, Q1, indicating that both the FAD and iron-sulfur cluster are properly inserted
GO:0005743 mitochondrial inner membrane	IDA PMID:8306995 Molecular cloning and expression of a cDNA encoding human el...	ACCEPT	Summary: Direct evidence that the mature ETF-QO resides in the inner mitochondrial membrane. Core location. Reason: Experimental localization of the processed 64-kDa mature protein to the mitochondrial (inner) membrane; matches structural data. Supporting Evidence: PMID:8306995 Electron-transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) in the inner mitochondrial membrane accepts electrons from electron-transfer flavoprotein
GO:0009055 electron transfer activity	IDA PMID:12049629 Expression of human electron transfer flavoprotein-ubiquinon...	KEEP AS NON CORE	Summary: ETF-QO functions as an electron carrier, transferring electrons from ETF to ubiquinone. Correct, though broader than the specific dehydrogenase activity. Reason: Accurate description of the electron-carrier property; kept as a correct but more general companion to the specific GO:0004174 core function. Supporting Evidence: PMID:12049629 a component of an electron-transfer system that links 10 different mitochondrial flavoprotein dehydrogenases to the mitochondrial bc1 complex
GO:0009055 electron transfer activity	IDA PMID:8306995 Molecular cloning and expression of a cDNA encoding human el...	KEEP AS NON CORE	Summary: ETF-QO transfers electrons from ETF to ubiquinone, acting as an electron carrier in the relay to the respiratory chain. Reason: Correct electron-carrier description; retained as a general companion to the specific dehydrogenase activity. Supporting Evidence: PMID:8306995 The detergent-solubilized protein transfers electrons from ETF to the ubiquinone homolog, Q1
GO:0022900 electron transport chain	IDA PMID:12049629 Expression of human electron transfer flavoprotein-ubiquinon...	ACCEPT	Summary: ETF-QO participates in the mitochondrial electron transport chain, linking flavoprotein dehydrogenases to the bc1 complex via ubiquinone. Reason: Direct evidence for the enzyme's role in feeding electrons into the respiratory electron transport chain via the ubiquinone pool. Supporting Evidence: PMID:12049629 links 10 different mitochondrial flavoprotein dehydrogenases to the mitochondrial bc1 complex via electron transfer flavoprotein (ETF) and ubiquinone
GO:0022900 electron transport chain	IDA PMID:8306995 Molecular cloning and expression of a cDNA encoding human el...	ACCEPT	Summary: ETF-QO reduces ubiquinone in the mitochondrial membrane, participating in the electron transport chain. Reason: Direct evidence that the enzyme reduces ubiquinone, its role in the respiratory electron transport chain. Supporting Evidence: PMID:8306995 reduces ubiquinone in the mitochondrial membrane
GO:0031966 mitochondrial membrane	IDA PMID:12049629 Expression of human electron transfer flavoprotein-ubiquinon...	KEEP AS NON CORE	Summary: ETF-QO is an integral mitochondrial membrane protein; correct but a broad parent of the specific inner-membrane location. Reason: Accurate but less specific than mitochondrial inner membrane (GO:0005743); kept as a broader, non-core localization. Supporting Evidence: PMID:12049629 ETF-QO is an integral membrane protein
GO:0050660 flavin adenine dinucleotide binding	ISS PMID:17050691 Structure of electron transfer flavoprotein-ubiquinone oxido...	ACCEPT	Summary: ETF-QO carries one FAD cofactor essential for electron transfer; supported by the structure of the porcine ortholog (source of ISS) and confirmed for the human enzyme. Reason: FAD binding is a core cofactor function; the crystal structure defines the FAD site, and the human enzyme is spectroscopically shown to contain one FAD equivalent. Correct and specific. Supporting Evidence: PMID:17050691 Three functional regions bind FAD, the 4Fe4S cluster, and UQ PMID:18037314 each contain a single [4Fe-4S](2+,1+) cluster and one equivalent of FAD

Gene Description

Existing Annotations Review

Core Functions

Electron-transferring-flavoprotein dehydrogenase (ETF-QO, EC 1.5.5.1): oxidizes reduced electron-transfer flavoprotein and reduces ubiquinone in the mitochondrial inner membrane, using bound FAD and a [4Fe-4S] cluster as redox relays.

Ubiquinone binding at a single hydrophobic site per monomer, positioning the physiological electron acceptor for reduction to ubiquinol.

FAD cofactor binding; the flavin is a core redox center that shuttles electrons from reduced ETF toward ubiquinone.

[4Fe-4S] cluster binding; a single iron-sulfur cluster serves as the second redox center of ETF-QO.

Links fatty-acid beta-oxidation (acyl-CoA dehydrogenase branch) to the respiratory chain by accepting the electrons generated during acyl-CoA dehydrogenation via ETF; loss of ETFDH blocks this flux and causes multiple acyl-CoA dehydrogenase deficiency.

References

📚 Additional Documentation

Notes

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