NDUFS3

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0045271 respiratory chain complex I	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation of NDUFS3 as part of respiratory chain complex I. This is the correct, well-supported complex-membership assignment and reflects the deeply conserved role of the 30 kDa/S3 core subunit across eukaryotes and its bacterial NuoC ortholog. Reason: NDUFS3 is a conserved core subunit of Complex I; complex membership is directly demonstrated by immunopurification and structural studies (PMID:12611891, PMID:28844695). GO:0045271 is the current, non-obsolete term for Complex I membership. Supporting Evidence: file:human/NDUFS3/NDUFS3-uniprot.txt Core subunit of the mitochondrial membrane respiratory chain
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (IEA) annotation to the mitochondrial inner membrane, consistent with the curated subcellular location and independently supported by experimental IDA annotations (PMID:18826940). Reason: Correct anatomical location. NDUFS3 is a peripheral membrane component of Complex I on the matrix side of the inner membrane. Supporting Evidence: file:human/NDUFS3/NDUFS3-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane
GO:0006120 mitochondrial electron transport, NADH to ubiquinone	IEA GO_REF:0000117	ACCEPT	Summary: Electronic (IEA, ARBA) annotation to the core Complex I biological process, electron transport from NADH to ubiquinone. This is the central physiological role of the complex NDUFS3 is part of and is redundantly supported by experimental IMP annotations. Reason: Core BP of Complex I; well supported by disease-variant functional studies showing NDUFS3 mutations abolish NADH:ubiquinone electron transfer (PMID:14729820, PMID:30140060). Supporting Evidence: file:human/NDUFS3/NDUFS3-uniprot.txt NADH through the respiratory chain, using ubiquinone as an electron
GO:0008137 NADH dehydrogenase (ubiquinone) activity	IEA GO_REF:0000120	MODIFY	Summary: Electronic (IEA) annotation of the complex-level catalytic activity NADH dehydrogenase (ubiquinone) activity (EC 7.1.1.2, RHEA:29091) with the enables qualifier. This is the holoenzyme activity of Complex I; NDUFS3 is a core structural subunit that contributes to but does not independently possess this activity. Reason: The catalytic activity is a property of the assembled complex, not of NDUFS3 in isolation (NDUFS3 carries no redox cofactor). The complex-level MF is best expressed with the contributes_to qualifier (as in the curated IMP annotation from PMID:30140060), rather than enables. Retain the term but with contributes_to. Proposed replacements: NADH dehydrogenase (ubiquinone) activity Supporting Evidence: file:human/NDUFS3/NDUFS3-uniprot.txt catalytic activity and assembly of complex I
GO:0016651 oxidoreductase activity, acting on NAD(P)H	IEA GO_REF:0000002	ACCEPT	Summary: Electronic (InterPro2GO) annotation to the broad parent MF oxidoreductase activity, acting on NAD(P)H. This is a correct but general ancestor of the specific NADH dehydrogenase (ubiquinone) activity. Reason: A correct, if general, MF ancestor consistent with the complex-level activity. IEA terms may legitimately be broader than the experimentally supported specific term.
GO:0045271 respiratory chain complex I	IEA GO_REF:0000117	ACCEPT	Summary: Electronic (IEA, ARBA) complex-membership annotation, redundant with the IBA and IDA annotations to the same term. Reason: Correct Complex I membership; duplicates are acceptable and reinforce the assignment. Supporting Evidence: file:human/NDUFS3/NDUFS3-uniprot.txt Core subunit of the mitochondrial membrane respiratory chain
GO:1902600 proton transmembrane transport	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: Electronic annotation (inferred from GO:0008137 via inter-ontology links) to proton transmembrane transport. Complex I couples NADH:ubiquinone electron transfer to translocation of protons across the inner membrane, so this is valid at the complex level, but for NDUFS3 (a peripheral-arm subunit not part of the membrane proton pump) it is a downstream/complex-level consequence rather than a core function. Reason: Proton pumping is performed by the membrane arm; NDUFS3 sits in the peripheral arm. The term is not wrong at the complex level but is peripheral to NDUFS3's own role. Supporting Evidence: PMID:9878551 which is accompanied by translocation of protons from the mitochondrial matrix to the intermembrane space
GO:0005515 protein binding	IPI PMID:15250827 Structural organization of mitochondrial human complex I: ro...	MARK AS OVER ANNOTATED	Summary: Bare protein binding IPI from a study of Complex I structural organization. Provides no specific molecular-function information. Reason: Per curation guidelines the uninformative protein binding term is not retained as a function. Biologically meaningful interactions of NDUFS3 (with other Complex I subunits and assembly factors) are captured by the complex-membership and assembly annotations.
GO:0005515 protein binding	IPI PMID:19688755 LC-MS/MS as an alternative for SDS-PAGE in blue native analy...	MARK AS OVER ANNOTATED	Summary: Bare protein binding IPI derived from a blue-native/LC-MS-MS methods study. No specific molecular function is conveyed. Reason: Uninformative protein binding; meaningful interactions are covered elsewhere.
GO:0005515 protein binding	IPI PMID:21310150 NDUFB7 and NDUFA8 are located at the intermembrane surface o...	MARK AS OVER ANNOTATED	Summary: Bare protein binding IPI from a study localizing NDUFB7/NDUFA8 in Complex I. No specific molecular function is conveyed for NDUFS3. Reason: Uninformative protein binding; complex membership is already captured by GO:0045271.
GO:0005515 protein binding	IPI PMID:24344204 TIMMDC1/C3orf1 functions as a membrane-embedded mitochondria...	MARK AS OVER ANNOTATED	Summary: Bare protein binding IPI from a study of the assembly factor TIMMDC1/MCIA complex. No specific molecular function is conveyed. Reason: Uninformative protein binding; the biologically relevant assembly context is captured by GO:0032981 (Complex I assembly).
GO:0005515 protein binding	IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat...	MARK AS OVER ANNOTATED	Summary: Bare protein binding IPI from a mitochondrial protein-interaction mapping study. No specific molecular function is conveyed. Reason: Uninformative protein binding; meaningful partners are captured by complex and assembly annotations.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Bare protein binding IPI from a large-scale human interactome study. No specific molecular function is conveyed. Reason: Uninformative protein binding; high-throughput interactome data do not add a specific function beyond known Complex I membership.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Bare protein binding IPI from the HuRI binary interactome reference map. No specific molecular function is conveyed. Reason: Uninformative protein binding from a genome-scale two-hybrid screen.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Bare protein binding IPI from a neurodegenerative-disease interactome study. No specific molecular function is conveyed. Reason: Uninformative protein binding.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Bare protein binding IPI from the BioPlex proteome-scale interactome. No specific molecular function is conveyed. Reason: Uninformative protein binding.
GO:0005743 mitochondrial inner membrane	IDA PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ...	ACCEPT	Summary: Experimental (IDA, ComplexPortal) localization of NDUFS3 to the mitochondrial inner membrane, from cryo-EM of the human respiratory megacomplex I2III2IV2, in which Complex I (including NDUFS3) is resolved in the inner membrane. Reason: Correct, structurally supported anatomical location for the Complex I holoenzyme containing NDUFS3. Supporting Evidence: PMID:28844695 the human respiratory chain megacomplex-I2III2IV2 (MCI2III2IV2) with 140 subunits
GO:0009060 aerobic respiration	NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-...	KEEP AS NON CORE	Summary: Author-statement (NAS, ComplexPortal) annotation of the Complex I holoenzyme to aerobic respiration. This is a valid complex-level physiological role but a broad, high-level process rather than NDUFS3's specific molecular contribution. Reason: Complex I is essential for aerobic respiration/OXPHOS, but this general process term is peripheral to NDUFS3's core electron-transport/assembly role and is better captured by GO:0006120. Supporting Evidence: PMID:30030361 The assembly of the five oxidative phosphorylation system (OXPHOS) complexes
GO:0042776 proton motive force-driven mitochondrial ATP synthesis	NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-...	KEEP AS NON CORE	Summary: Author-statement (NAS, ComplexPortal) annotation to proton motive force-driven mitochondrial ATP synthesis, reflecting Complex I's contribution to the proton-motive force. ATP synthesis itself is carried out by Complex V; Complex I contributes upstream via proton pumping. Reason: A downstream, complex-level physiological consequence. Not a core molecular function of NDUFS3, which is a peripheral-arm structural/catalytic subunit. Supporting Evidence: PMID:30030361 oxidative phosphorylation system (OXPHOS)
GO:0045271 respiratory chain complex I	IPI PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ...	ACCEPT	Summary: Experimental (IPI, ComplexPortal) annotation of NDUFS3 as part of respiratory chain complex I, from the cryo-EM megacomplex structure resolving Complex I subunits. Reason: Directly supported Complex I membership from a structural study. Supporting Evidence: PMID:28844695 the precise assignment of individual subunits of human CI and CIII
GO:0005739 mitochondrion	IDA GO_REF:0000052	ACCEPT	Summary: Experimental (IDA, HPA immunofluorescence) localization to the mitochondrion. Correct but less specific than the inner-membrane annotation. Reason: Correct general localization; consistent with the more specific GO:0005743 annotation.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput (HTP) mitochondrial-proteome localization to the mitochondrion. Consistent with all other localization evidence. Reason: Correct general localization; NDUFS3 is a bona fide component of the human mitochondrial proteome.
GO:0045271 respiratory chain complex I	IDA PMID:12611891 The subunit composition of the human NADH dehydrogenase obta...	ACCEPT	Summary: Experimental (IDA) Complex I membership from one-step immunopurification and mass-spectrometric identification of the human NADH dehydrogenase subunit composition, in which NDUFS3 was identified as a bona fide subunit. Reason: Direct biochemical evidence for Complex I membership. Supporting Evidence: PMID:12611891 an immunocapture procedure for isolating this multisubunit membrane-bound complex from human tissue
GO:0045271 respiratory chain complex I	IDA PMID:17209039 Identification of mitochondrial complex I assembly intermedi...	ACCEPT	Summary: Experimental (IDA) Complex I membership; NDUFS3 was tagged and traced through Complex I assembly intermediates, confirming it is an integral subunit of the assembled complex. Reason: Direct evidence; NDUFS3-GFP incorporates into the fully assembled Complex I. Supporting Evidence: PMID:17209039 six distinct NDUFS3-GFP-containing subcomplexes gradually appeared
GO:0045271 respiratory chain complex I	IDA PMID:18826940 Subunits of mitochondrial complex I exist as part of matrix-...	ACCEPT	Summary: Experimental (IDA) Complex I membership; NDUFS3 was among the GFP-tagged subunits shown to be present in the immobile holoenzyme fraction as well as a matrix-soluble subassembly. Reason: Direct evidence for Complex I membership from live-cell subassembly analysis. Supporting Evidence: PMID:18826940 each subunit was partially present in a virtually immobile fraction, possibly representing the holo-enzyme
GO:0045271 respiratory chain complex I	IDA PMID:31536960 Rewiring of the Human Mitochondrial Interactome during Neuro...	ACCEPT	Summary: Experimental (IDA) Complex I membership from a mitochondrial interactome study that also identified the NDUFS3-RAB5IF interaction. Reason: Consistent with all other Complex I membership evidence. Supporting Evidence: PMID:31536960 Regulators of the Respirasome
GO:0045271 respiratory chain complex I	NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox...	ACCEPT	Summary: Author-statement (NAS) Complex I membership from the cDNA characterization of the nuclear-encoded Complex I subunits, describing NADH:ubiquinone oxidoreductase as a multiprotein complex of the inner mitochondrial membrane. Reason: Correct membership; redundant with stronger experimental evidence. Supporting Evidence: PMID:9878551 NADH:ubiquinone oxidoreductase (complex I) is an extremely complicated multiprotein complex located in the inner mitochondrial membrane
GO:0008137 NADH dehydrogenase (ubiquinone) activity	IMP PMID:30140060 A Novel NDUFS3 mutation in a Chinese patient with severe Lei...	ACCEPT	Summary: Experimental (IMP) annotation with the contributes_to qualifier: a novel NDUFS3 variant (R140W) in a Chinese Leigh syndrome patient decreased NDUFS3 amount and Complex I assembly, demonstrating that NDUFS3 contributes to the complex-level NADH:ubiquinone catalytic activity. This is the correctly-framed core molecular function for a structural core subunit. Reason: contributes_to GO:0008137 is the appropriate MF for a core subunit that is required for, but does not independently possess, the complex-level catalytic activity. Loss of function reduces Complex I activity/assembly. Supporting Evidence: PMID:30140060 decreased amount of NDUFS3 and complex I assembly when compared with two control cells
GO:0005743 mitochondrial inner membrane	IDA PMID:18826940 Subunits of mitochondrial complex I exist as part of matrix-...	ACCEPT	Summary: Experimental (IDA) inner-membrane localization with topology (matrix side) determined by submitochondrial FRAP of GFP-tagged NDUFS3. Reason: Direct, well-controlled evidence for the curated subcellular location. Supporting Evidence: PMID:18826940 matrix- and membrane-associated subcomplexes in living cells
GO:0006120 mitochondrial electron transport, NADH to ubiquinone	IMP PMID:14729820 Mutant NDUFS3 subunit of mitochondrial complex I causes Leig...	ACCEPT	Summary: Experimental (IMP) annotation to the core Complex I biological process. NDUFS3 mutations identified in Leigh syndrome patients cause Complex I deficiency, directly implicating NDUFS3 in NADH-to-ubiquinone electron transport. Reason: This is a core biological process of NDUFS3. Mutations abolish/reduce NADH:ubiquinone electron transfer, causing complex I deficiency. Supporting Evidence: PMID:14729820 coding for the seventh and last subunit of complex I core, were shown to cause late onset Leigh syndrome, optic atrophy, and complex I deficiency
GO:0006120 mitochondrial electron transport, NADH to ubiquinone	IMP PMID:30140060 A Novel NDUFS3 mutation in a Chinese patient with severe Lei...	ACCEPT	Summary: Experimental (IMP) annotation to the core Complex I biological process from a second Leigh syndrome patient with NDUFS3 variants and demonstrated Complex I deficiency. Reason: Core BP; independently supports GO:0006120 for NDUFS3. Supporting Evidence: PMID:30140060 two missense mutations of NDUFS3
GO:0008137 NADH dehydrogenase (ubiquinone) activity	IMP PMID:14729820 Mutant NDUFS3 subunit of mitochondrial complex I causes Leig...	MODIFY	Summary: Experimental (IMP) annotation of the complex-level NADH dehydrogenase (ubiquinone) activity with the enables qualifier, from NDUFS3 disease-variant characterization. NDUFS3 is required for this activity but, as a cofactor-less structural subunit, does not carry it out independently. Reason: The activity is a property of the assembled complex. contributes_to is the more accurate qualifier (as used in the PMID:30140060 IMP annotation). Retain the term with contributes_to rather than enables. Proposed replacements: NADH dehydrogenase (ubiquinone) activity Supporting Evidence: PMID:14729820 coding for the seventh and last subunit of complex I core
GO:0032981 mitochondrial respiratory chain complex I assembly	IMP PMID:30140060 A Novel NDUFS3 mutation in a Chinese patient with severe Lei...	ACCEPT	Summary: Experimental (IMP) annotation to Complex I assembly. NDUFS3 patient variants reduced NDUFS3 protein levels and impaired Complex I assembly in patient-derived cells, consistent with NDUFS3 acting as an early nucleation point of the peripheral arm (PMID:17209039). Reason: Core biological process. NDUFS3 is required for correct stepwise assembly of Complex I; its loss impairs assembly. Supporting Evidence: PMID:30140060 decreased amount of NDUFS3 and complex I assembly when compared with two control cells
GO:0005515 protein binding	IPI PMID:31536960 Rewiring of the Human Mitochondrial Interactome during Neuro...	MARK AS OVER ANNOTATED	Summary: Curated protein binding IPI capturing the NDUFS3-RAB5IF interaction. While this is a genuine curated interaction, the bare protein binding term itself is uninformative as a molecular function. Reason: Per curation guidelines protein binding is not retained as an informative function. The interaction is noted, but conveys no specific molecular activity. Supporting Evidence: PMID:31536960 Regulators of the Respirasome and Neurogenesis
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-163217	KEEP AS NON CORE	Summary: Reactome TAS annotation to the mitochondrial matrix, from the reaction in which Complex I oxidizes NADH and reduces CoQ. NDUFS3 is a matrix-side peripheral-arm subunit, so the matrix location is compatible, though the primary curated anatomical location is the inner membrane (GO:0005743). Reason: Compatible with NDUFS3's matrix-facing topology but less precise than the inner-membrane annotation; retained as non-core localization context.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-6799178	KEEP AS NON CORE	Summary: Reactome TAS annotation to the mitochondrial matrix from a Complex I biogenesis reaction (Intermediate 1 binds HP subcomplex to form Intermediate 2). Reason: Assembly-intermediate localization context; compatible with matrix-side topology but less precise than GO:0005743.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-6799179	KEEP AS NON CORE	Summary: Reactome TAS annotation to the mitochondrial matrix from a Complex I biogenesis reaction (peripheral arm subunits bind the 815 kDa complex). Reason: Assembly-intermediate localization context; less precise than GO:0005743.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-6799191	KEEP AS NON CORE	Summary: Reactome TAS annotation to the mitochondrial matrix from a Complex I biogenesis reaction (Intermediate 2 binds MT-ND1:NDUFAF5:NDUFAF6). Reason: Assembly-intermediate localization context; less precise than GO:0005743.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-6799196	KEEP AS NON CORE	Summary: Reactome TAS annotation to the mitochondrial matrix from a Complex I biogenesis reaction (dissociation of assembly factors to form Complex I). Reason: Assembly-intermediate localization context; less precise than GO:0005743.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-6799197	KEEP AS NON CORE	Summary: Reactome TAS annotation to the mitochondrial matrix from a Complex I biogenesis reaction (ND4, ND5 bind the 550 kDa complex). Reason: Assembly-intermediate localization context; less precise than GO:0005743.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-6799202	KEEP AS NON CORE	Summary: Reactome TAS annotation to the mitochondrial matrix from a Complex I biogenesis reaction (315 kDa binds 370 kDa to form 550 kDa complex). Reason: Assembly-intermediate localization context; less precise than GO:0005743.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-6799203	KEEP AS NON CORE	Summary: Reactome TAS annotation to the mitochondrial matrix from a Complex I biogenesis reaction (IP subcomplex binds NDUFAF3, NDUFAF4, TIMMDC1). NDUFS3 is part of the IP subcomplex referenced here. Reason: Assembly-intermediate localization context; less precise than GO:0005743.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-6800868	KEEP AS NON CORE	Summary: Reactome TAS annotation to the mitochondrial matrix from the reaction forming the IP subcomplex, of which NDUFS3 is a component. Reason: Assembly-intermediate localization context; less precise than GO:0005743.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838035	KEEP AS NON CORE	Summary: Reactome TAS annotation to the mitochondrial matrix from a mitochondrial protein quality-control reaction (CLPXP binds matrix proteins). This reflects NDUFS3 as a potential CLPXP substrate rather than a Complex I function. Reason: Localization is compatible but the reaction is a generic matrix quality-control context, not a core NDUFS3 function.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838289	KEEP AS NON CORE	Summary: Reactome TAS annotation to the mitochondrial matrix from a mitochondrial protein quality-control reaction (CLPXP degrades matrix proteins). Reason: Generic matrix quality-control context, not a core NDUFS3 function; localization is compatible.
GO:0005515 protein binding	IPI PMID:19822128 DJ-1 binds to mitochondrial complex I and maintains its acti...	MARK AS OVER ANNOTATED	Summary: protein binding IPI from the study showing DJ-1 (PARK7) binds Complex I and maintains its activity. The bare protein binding term is uninformative as a molecular function. Reason: Per curation guidelines protein binding is not retained. Note the study primarily demonstrated DJ-1 binding to NDUFA4 and ND1, not directly to NDUFS3. Supporting Evidence: PMID:19822128 DJ-1 directly bound to NDUFA4 and ND1
GO:0021762 substantia nigra development	HEP PMID:22926577 Quantitative proteomic analysis of human substantia nigra in...	MARK AS OVER ANNOTATED	Summary: HEP (inferred from high-throughput expression) annotation to substantia nigra development, from a differential proteomics survey of human substantia nigra in neurodegenerative disease. This reflects differential NDUFS3 expression/abundance, not a role in the development of the substantia nigra. Reason: The evidence is a differential-abundance proteomics comparison in disease tissue; it does not establish a developmental function for NDUFS3. This is an over-annotation driven by expression detection in substantia nigra. Supporting Evidence: PMID:22926577 Using a quantitative proteomic approach, we investigated protein expressions in the substantia nigra
GO:0072593 reactive oxygen species metabolic process	IMP PMID:16826196 Coupling mitochondrial respiratory chain to cell death: an e...	KEEP AS NON CORE	Summary: Experimental (IMP) annotation to reactive oxygen species metabolic process. siRNA knockdown of NDUFS3 in cancer cell lines reduced ROS production and conferred resistance to IFN-beta/RA-induced apoptosis. This is a downstream physiological consequence of reduced Complex I function rather than a core molecular role of NDUFS3. Reason: Reduced ROS on NDUFS3 knockdown reflects loss of Complex I activity (a known ROS source), a secondary/downstream effect. Retained as a non-core process. Supporting Evidence: PMID:16826196 two subunits of MRC complex I, by siRNA in two cancer cell lines conferred resistance to IFN-beta/RA-induced apoptosis and reduced ROS production
GO:0005515 protein binding	IPI PMID:19463981 Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66...	MARK AS OVER ANNOTATED	Summary: Curated protein binding IPI capturing the interaction between NDUFS3 and the Complex I assembly factor NDUFAF3. Although a genuine, biologically meaningful interaction, the bare protein binding term itself conveys no specific molecular function. Reason: Per curation guidelines protein binding is not retained as a function. The assembly-factor interaction is relevant context for GO:0032981 (Complex I assembly). Supporting Evidence: PMID:19463981 NDUFAF3 is a genuine mitochondrial complex I assembly protein that interacts with complex I subunits
GO:0003954 NADH dehydrogenase activity	IMP PMID:16826196 Coupling mitochondrial respiratory chain to cell death: an e...	MARK AS OVER ANNOTATED	Summary: Experimental (IMP) annotation to the broader NADH dehydrogenase activity, from the NDUFS3 siRNA-knockdown study affecting Complex I function. This is a looser parent of the specific NADH dehydrogenase (ubiquinone) activity and, like the specific term, is a complex-level activity NDUFS3 contributes to rather than independently enables. Reason: Broader/looser than the specific GO:0008137 already captured with contributes_to, and framed as enables for a cofactor-less structural subunit. The specific complex-level term is preferred. Supporting Evidence: PMID:16826196 NDUFS3 (NADH dehydrogenase (ubiquinone) Fe-S protein 3), two subunits of MRC complex I
GO:0003954 NADH dehydrogenase activity	IMP PMID:11112787 Human complex I defects can be resolved by monoclonal antibo...	MARK AS OVER ANNOTATED	Summary: Experimental (IMP) annotation to NADH dehydrogenase activity from a monoclonal antibody study of Complex I subunit assembly patterns (the 30 kDa subunit is NDUFS3). A broad complex-level activity term framed with enables. Reason: Broader than the specific GO:0008137 captured as contributes_to; the activity is a complex-level property, not independently enabled by NDUFS3. Supporting Evidence: PMID:11112787 a new set of monoclonal antibodies that react with 39-, 30-, 20-, 18-, 15-, and 8-kDa subunits of Complex I
GO:0006120 mitochondrial electron transport, NADH to ubiquinone	NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox...	ACCEPT	Summary: Author-statement (NAS) annotation to the core Complex I biological process, from the cDNA characterization paper describing Complex I's main function as transport of electrons from NADH to ubiquinone. Reason: Correct core BP; redundant with the experimental IMP annotations. Supporting Evidence: PMID:9878551 Its main function is the transport of electrons from NADH to ubiquinone
GO:0008137 NADH dehydrogenase (ubiquinone) activity	NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox...	MODIFY	Summary: Author-statement (NAS) annotation of the complex-level NADH dehydrogenase (ubiquinone) activity with enables, from the cDNA characterization paper. Reason: The activity is a property of the assembled complex; contributes_to is more accurate for this cofactor-less core subunit than enables. Retain term with contributes_to. Proposed replacements: NADH dehydrogenase (ubiquinone) activity Supporting Evidence: PMID:9878551 NADH:ubiquinone oxidoreductase (complex I)
GO:0005739 mitochondrion	NAS PMID:9647766 cDNA sequence and chromosomal localization of the remaining ...	ACCEPT	Summary: Author-statement (NAS) mitochondrial localization from the cDNA cloning of the human IP-fraction Complex I subunits including NDUFS3 (30 kDa). Reason: Correct general localization, consistent with all other evidence. Supporting Evidence: PMID:9647766 NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial respiratory chain
GO:0006120 mitochondrial electron transport, NADH to ubiquinone	NAS PMID:9647766 cDNA sequence and chromosomal localization of the remaining ...	ACCEPT	Summary: Author-statement (NAS) annotation to the core Complex I biological process, from the cDNA cloning paper of the IP-fraction subunits. Reason: Correct core BP; redundant with experimental IMP annotations. Supporting Evidence: PMID:9647766 NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial respiratory chain
GO:0008137 NADH dehydrogenase (ubiquinone) activity	NAS PMID:9647766 cDNA sequence and chromosomal localization of the remaining ...	MODIFY	Summary: Author-statement (NAS) annotation of the complex-level NADH dehydrogenase (ubiquinone) activity with enables, from the IP-fraction cDNA cloning paper. Reason: Complex-level activity; contributes_to is more accurate than enables for this cofactor-less structural subunit. Retain term with contributes_to. Proposed replacements: NADH dehydrogenase (ubiquinone) activity Supporting Evidence: PMID:9647766 important prosthetic groups highly conserved among species
GO:0009055 electron transfer activity	NAS PMID:9647766 cDNA sequence and chromosomal localization of the remaining ...	MARK AS OVER ANNOTATED	Summary: Author-statement (NAS) annotation to electron transfer activity. In Complex I, the electron-transfer chemistry is carried out by the flavin (in NDUFV1) and the chain of iron-sulfur clusters (in NDUFV1/NDUFV2/NDUFS1/NDUFS7/NDUFS8 etc.). NDUFS3, despite its historical "iron-sulfur protein 3" name, carries no redox cofactor and does not itself transfer electrons. Reason: NDUFS3 is a cofactor-less structural core subunit; it does not carry a redox center and does not itself have electron transfer activity. Assigning this MF to NDUFS3 is an over-annotation stemming from the misleading "IP/iron-sulfur protein" naming. Supporting Evidence: PMID:9647766 it contains important prosthetic groups highly conserved among species
GO:0031966 mitochondrial membrane	IDA PMID:17209039 Identification of mitochondrial complex I assembly intermedi...	ACCEPT	Summary: Experimental (IDA) annotation to the mitochondrial membrane, from the tagged-NDUFS3 assembly-tracing study. Consistent with, but less specific than, the inner-membrane annotation. Reason: Correct, if general, membrane localization; subsumed by the more specific GO:0005743. Supporting Evidence: PMID:17209039 the entry point of mitochondrial subunits
GO:0005198 structural molecule activity	IMP PMID:30140060 A Novel NDUFS3 mutation in a Chinese patient with severe Lei...	NEW	Summary: Proposed subunit-specific molecular function. NDUFS3 is a cofactor-less core structural subunit of the Complex I peripheral (Q-module) arm; its own molecular role is to provide a structural scaffold required for holoenzyme assembly and catalysis, rather than to independently carry out the complex-level NADH:ubiquinone oxidoreductase reaction. This captures the structural-constituent role that underlies the contributes_to GO:0008137 annotation. Reason: NDUFS3 loss-of-function reduces both Complex I assembly and activity, consistent with a structural constituent role. Added to reflect the subunit-specific MF paired with the complex-level contributes_to GO:0008137 activity in core_functions. Supporting Evidence: PMID:30140060 decreased amount of NDUFS3 and complex I assembly when compared with two control cells file:human/NDUFS3/NDUFS3-uniprot.txt catalytic activity and assembly of complex I

📄 View Raw YAML

id: O75489
gene_symbol: NDUFS3
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: NDUFS3 (NADH:ubiquinone oxidoreductase core subunit S3, historically the "30 kDa" subunit
  and confusingly named "iron-sulfur protein 3", although it carries no redox cofactor of its own) is
  one of the seven conserved nuclear-encoded core subunits of mitochondrial respiratory Complex I (NADH:ubiquinone
  oxidoreductase, EC 7.1.1.2). It is a structural core component of the Q-module in the hydrophilic peripheral
  arm, sitting near the ubiquinone-reduction site adjacent to the iron-sulfur subunit NDUFS2. NDUFS3 is
  required both for the catalytic activity of Complex I (electron transfer from NADH to ubiquinone coupled
  to proton translocation across the inner membrane) and for its stepwise assembly, acting as an early
  nucleation point of the peripheral arm. The protein is imported into mitochondria (cleaved N-terminal
  transit peptide) and localizes to the matrix side of the mitochondrial inner membrane as a peripheral
  membrane component of the Complex I holoenzyme. Biallelic loss-of-function variants cause mitochondrial
  complex I deficiency (nuclear type 8, MC1DN8), presenting clinically as Leigh syndrome and optic atrophy.
alternative_products:
- name: '1'
  id: O75489-1
- name: '2'
  id: O75489-2
  sequence_note: VSP_057065, VSP_057066
existing_annotations:
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic (IBA) annotation of NDUFS3 as part of respiratory chain complex I. This is the
      correct, well-supported complex-membership assignment and reflects the deeply conserved role of
      the 30 kDa/S3 core subunit across eukaryotes and its bacterial NuoC ortholog.
    action: ACCEPT
    reason: NDUFS3 is a conserved core subunit of Complex I; complex membership is directly demonstrated
      by immunopurification and structural studies (PMID:12611891, PMID:28844695). GO:0045271 is the current,
      non-obsolete term for Complex I membership.
    supported_by:
    - reference_id: file:human/NDUFS3/NDUFS3-uniprot.txt
      supporting_text: Core subunit of the mitochondrial membrane respiratory chain
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic (IEA) annotation to the mitochondrial inner membrane, consistent with the curated
      subcellular location and independently supported by experimental IDA annotations (PMID:18826940).
    action: ACCEPT
    reason: Correct anatomical location. NDUFS3 is a peripheral membrane component of Complex I on the
      matrix side of the inner membrane.
    supported_by:
    - reference_id: file:human/NDUFS3/NDUFS3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion inner membrane'
- term:
    id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Electronic (IEA, ARBA) annotation to the core Complex I biological process, electron transport
      from NADH to ubiquinone. This is the central physiological role of the complex NDUFS3 is part of
      and is redundantly supported by experimental IMP annotations.
    action: ACCEPT
    reason: Core BP of Complex I; well supported by disease-variant functional studies showing NDUFS3
      mutations abolish NADH:ubiquinone electron transfer (PMID:14729820, PMID:30140060).
    supported_by:
    - reference_id: file:human/NDUFS3/NDUFS3-uniprot.txt
      supporting_text: NADH through the respiratory chain, using ubiquinone as an electron
- term:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic (IEA) annotation of the complex-level catalytic activity NADH dehydrogenase (ubiquinone)
      activity (EC 7.1.1.2, RHEA:29091) with the enables qualifier. This is the holoenzyme activity of
      Complex I; NDUFS3 is a core structural subunit that contributes to but does not independently possess
      this activity.
    action: MODIFY
    reason: The catalytic activity is a property of the assembled complex, not of NDUFS3 in isolation
      (NDUFS3 carries no redox cofactor). The complex-level MF is best expressed with the contributes_to
      qualifier (as in the curated IMP annotation from PMID:30140060), rather than enables. Retain the
      term but with contributes_to.
    proposed_replacement_terms:
    - id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    supported_by:
    - reference_id: file:human/NDUFS3/NDUFS3-uniprot.txt
      supporting_text: catalytic activity and assembly of complex I
- term:
    id: GO:0016651
    label: oxidoreductase activity, acting on NAD(P)H
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Electronic (InterPro2GO) annotation to the broad parent MF oxidoreductase activity, acting
      on NAD(P)H. This is a correct but general ancestor of the specific NADH dehydrogenase (ubiquinone)
      activity.
    action: ACCEPT
    reason: A correct, if general, MF ancestor consistent with the complex-level activity. IEA terms may
      legitimately be broader than the experimentally supported specific term.
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: part_of
  review:
    summary: Electronic (IEA, ARBA) complex-membership annotation, redundant with the IBA and IDA annotations
      to the same term.
    action: ACCEPT
    reason: Correct Complex I membership; duplicates are acceptable and reinforce the assignment.
    supported_by:
    - reference_id: file:human/NDUFS3/NDUFS3-uniprot.txt
      supporting_text: Core subunit of the mitochondrial membrane respiratory chain
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: Electronic annotation (inferred from GO:0008137 via inter-ontology links) to proton transmembrane
      transport. Complex I couples NADH:ubiquinone electron transfer to translocation of protons across
      the inner membrane, so this is valid at the complex level, but for NDUFS3 (a peripheral-arm subunit
      not part of the membrane proton pump) it is a downstream/complex-level consequence rather than a
      core function.
    action: KEEP_AS_NON_CORE
    reason: Proton pumping is performed by the membrane arm; NDUFS3 sits in the peripheral arm. The term
      is not wrong at the complex level but is peripheral to NDUFS3's own role.
    supported_by:
    - reference_id: PMID:9878551
      supporting_text: which is accompanied by translocation of protons from the mitochondrial matrix
        to the intermembrane space
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15250827
  qualifier: enables
  review:
    summary: Bare protein binding IPI from a study of Complex I structural organization. Provides no specific
      molecular-function information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per curation guidelines the uninformative protein binding term is not retained as a function.
      Biologically meaningful interactions of NDUFS3 (with other Complex I subunits and assembly factors)
      are captured by the complex-membership and assembly annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19688755
  qualifier: enables
  review:
    summary: Bare protein binding IPI derived from a blue-native/LC-MS-MS methods study. No specific molecular
      function is conveyed.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative protein binding; meaningful interactions are covered elsewhere.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21310150
  qualifier: enables
  review:
    summary: Bare protein binding IPI from a study localizing NDUFB7/NDUFA8 in Complex I. No specific
      molecular function is conveyed for NDUFS3.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative protein binding; complex membership is already captured by GO:0045271.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24344204
  qualifier: enables
  review:
    summary: Bare protein binding IPI from a study of the assembly factor TIMMDC1/MCIA complex. No specific
      molecular function is conveyed.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative protein binding; the biologically relevant assembly context is captured by GO:0032981
      (Complex I assembly).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27499296
  qualifier: enables
  review:
    summary: Bare protein binding IPI from a mitochondrial protein-interaction mapping study. No specific
      molecular function is conveyed.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative protein binding; meaningful partners are captured by complex and assembly annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Bare protein binding IPI from a large-scale human interactome study. No specific molecular
      function is conveyed.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative protein binding; high-throughput interactome data do not add a specific function
      beyond known Complex I membership.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Bare protein binding IPI from the HuRI binary interactome reference map. No specific molecular
      function is conveyed.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative protein binding from a genome-scale two-hybrid screen.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Bare protein binding IPI from a neurodegenerative-disease interactome study. No specific
      molecular function is conveyed.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Bare protein binding IPI from the BioPlex proteome-scale interactome. No specific molecular
      function is conveyed.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative protein binding.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:28844695
  qualifier: located_in
  review:
    summary: Experimental (IDA, ComplexPortal) localization of NDUFS3 to the mitochondrial inner membrane,
      from cryo-EM of the human respiratory megacomplex I2III2IV2, in which Complex I (including NDUFS3)
      is resolved in the inner membrane.
    action: ACCEPT
    reason: Correct, structurally supported anatomical location for the Complex I holoenzyme containing
      NDUFS3.
    supported_by:
    - reference_id: PMID:28844695
      supporting_text: the human respiratory chain megacomplex-I2III2IV2 (MCI2III2IV2) with 140 subunits
- term:
    id: GO:0009060
    label: aerobic respiration
  evidence_type: NAS
  original_reference_id: PMID:30030361
  qualifier: involved_in
  review:
    summary: Author-statement (NAS, ComplexPortal) annotation of the Complex I holoenzyme to aerobic respiration.
      This is a valid complex-level physiological role but a broad, high-level process rather than NDUFS3's
      specific molecular contribution.
    action: KEEP_AS_NON_CORE
    reason: Complex I is essential for aerobic respiration/OXPHOS, but this general process term is peripheral
      to NDUFS3's core electron-transport/assembly role and is better captured by GO:0006120.
    supported_by:
    - reference_id: PMID:30030361
      supporting_text: The assembly of the five oxidative phosphorylation system (OXPHOS) complexes
- term:
    id: GO:0042776
    label: proton motive force-driven mitochondrial ATP synthesis
  evidence_type: NAS
  original_reference_id: PMID:30030361
  qualifier: involved_in
  review:
    summary: Author-statement (NAS, ComplexPortal) annotation to proton motive force-driven mitochondrial
      ATP synthesis, reflecting Complex I's contribution to the proton-motive force. ATP synthesis itself
      is carried out by Complex V; Complex I contributes upstream via proton pumping.
    action: KEEP_AS_NON_CORE
    reason: A downstream, complex-level physiological consequence. Not a core molecular function of NDUFS3,
      which is a peripheral-arm structural/catalytic subunit.
    supported_by:
    - reference_id: PMID:30030361
      supporting_text: oxidative phosphorylation system (OXPHOS)
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IPI
  original_reference_id: PMID:28844695
  qualifier: part_of
  review:
    summary: Experimental (IPI, ComplexPortal) annotation of NDUFS3 as part of respiratory chain complex
      I, from the cryo-EM megacomplex structure resolving Complex I subunits.
    action: ACCEPT
    reason: Directly supported Complex I membership from a structural study.
    supported_by:
    - reference_id: PMID:28844695
      supporting_text: the precise assignment of individual subunits of human CI and CIII
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Experimental (IDA, HPA immunofluorescence) localization to the mitochondrion. Correct but
      less specific than the inner-membrane annotation.
    action: ACCEPT
    reason: Correct general localization; consistent with the more specific GO:0005743 annotation.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput (HTP) mitochondrial-proteome localization to the mitochondrion. Consistent
      with all other localization evidence.
    action: ACCEPT
    reason: Correct general localization; NDUFS3 is a bona fide component of the human mitochondrial proteome.
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IDA
  original_reference_id: PMID:12611891
  qualifier: part_of
  review:
    summary: Experimental (IDA) Complex I membership from one-step immunopurification and mass-spectrometric
      identification of the human NADH dehydrogenase subunit composition, in which NDUFS3 was identified
      as a bona fide subunit.
    action: ACCEPT
    reason: Direct biochemical evidence for Complex I membership.
    supported_by:
    - reference_id: PMID:12611891
      supporting_text: an immunocapture procedure for isolating this multisubunit membrane-bound complex
        from human tissue
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IDA
  original_reference_id: PMID:17209039
  qualifier: part_of
  review:
    summary: Experimental (IDA) Complex I membership; NDUFS3 was tagged and traced through Complex I assembly
      intermediates, confirming it is an integral subunit of the assembled complex.
    action: ACCEPT
    reason: Direct evidence; NDUFS3-GFP incorporates into the fully assembled Complex I.
    supported_by:
    - reference_id: PMID:17209039
      supporting_text: six distinct NDUFS3-GFP-containing subcomplexes gradually appeared
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IDA
  original_reference_id: PMID:18826940
  qualifier: part_of
  review:
    summary: Experimental (IDA) Complex I membership; NDUFS3 was among the GFP-tagged subunits shown to
      be present in the immobile holoenzyme fraction as well as a matrix-soluble subassembly.
    action: ACCEPT
    reason: Direct evidence for Complex I membership from live-cell subassembly analysis.
    supported_by:
    - reference_id: PMID:18826940
      supporting_text: each subunit was partially present in a virtually immobile fraction, possibly representing
        the holo-enzyme
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: IDA
  original_reference_id: PMID:31536960
  qualifier: part_of
  review:
    summary: Experimental (IDA) Complex I membership from a mitochondrial interactome study that also
      identified the NDUFS3-RAB5IF interaction.
    action: ACCEPT
    reason: Consistent with all other Complex I membership evidence.
    supported_by:
    - reference_id: PMID:31536960
      supporting_text: Regulators of the Respirasome
- term:
    id: GO:0045271
    label: respiratory chain complex I
  evidence_type: NAS
  original_reference_id: PMID:9878551
  qualifier: part_of
  review:
    summary: Author-statement (NAS) Complex I membership from the cDNA characterization of the nuclear-encoded
      Complex I subunits, describing NADH:ubiquinone oxidoreductase as a multiprotein complex of the inner
      mitochondrial membrane.
    action: ACCEPT
    reason: Correct membership; redundant with stronger experimental evidence.
    supported_by:
    - reference_id: PMID:9878551
      supporting_text: NADH:ubiquinone oxidoreductase (complex I) is an extremely complicated multiprotein
        complex located in the inner mitochondrial membrane
- term:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  evidence_type: IMP
  original_reference_id: PMID:30140060
  qualifier: contributes_to
  review:
    summary: 'Experimental (IMP) annotation with the contributes_to qualifier: a novel NDUFS3 variant
      (R140W) in a Chinese Leigh syndrome patient decreased NDUFS3 amount and Complex I assembly, demonstrating
      that NDUFS3 contributes to the complex-level NADH:ubiquinone catalytic activity. This is the correctly-framed
      core molecular function for a structural core subunit.'
    action: ACCEPT
    reason: contributes_to GO:0008137 is the appropriate MF for a core subunit that is required for, but
      does not independently possess, the complex-level catalytic activity. Loss of function reduces Complex
      I activity/assembly.
    supported_by:
    - reference_id: PMID:30140060
      supporting_text: decreased amount of NDUFS3 and complex I assembly when compared with two control
        cells
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:18826940
  qualifier: located_in
  review:
    summary: Experimental (IDA) inner-membrane localization with topology (matrix side) determined by
      submitochondrial FRAP of GFP-tagged NDUFS3.
    action: ACCEPT
    reason: Direct, well-controlled evidence for the curated subcellular location.
    supported_by:
    - reference_id: PMID:18826940
      supporting_text: matrix- and membrane-associated subcomplexes in living cells
- term:
    id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  evidence_type: IMP
  original_reference_id: PMID:14729820
  qualifier: involved_in
  review:
    summary: Experimental (IMP) annotation to the core Complex I biological process. NDUFS3 mutations
      identified in Leigh syndrome patients cause Complex I deficiency, directly implicating NDUFS3 in
      NADH-to-ubiquinone electron transport.
    action: ACCEPT
    reason: This is a core biological process of NDUFS3. Mutations abolish/reduce NADH:ubiquinone electron
      transfer, causing complex I deficiency.
    supported_by:
    - reference_id: PMID:14729820
      supporting_text: coding for the seventh and last subunit of complex I core, were shown to cause
        late onset Leigh syndrome, optic atrophy, and complex I deficiency
- term:
    id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  evidence_type: IMP
  original_reference_id: PMID:30140060
  qualifier: involved_in
  review:
    summary: Experimental (IMP) annotation to the core Complex I biological process from a second Leigh
      syndrome patient with NDUFS3 variants and demonstrated Complex I deficiency.
    action: ACCEPT
    reason: Core BP; independently supports GO:0006120 for NDUFS3.
    supported_by:
    - reference_id: PMID:30140060
      supporting_text: two missense mutations of NDUFS3
- term:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  evidence_type: IMP
  original_reference_id: PMID:14729820
  qualifier: enables
  review:
    summary: Experimental (IMP) annotation of the complex-level NADH dehydrogenase (ubiquinone) activity
      with the enables qualifier, from NDUFS3 disease-variant characterization. NDUFS3 is required for
      this activity but, as a cofactor-less structural subunit, does not carry it out independently.
    action: MODIFY
    reason: The activity is a property of the assembled complex. contributes_to is the more accurate qualifier
      (as used in the PMID:30140060 IMP annotation). Retain the term with contributes_to rather than enables.
    proposed_replacement_terms:
    - id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    supported_by:
    - reference_id: PMID:14729820
      supporting_text: coding for the seventh and last subunit of complex I core
- term:
    id: GO:0032981
    label: mitochondrial respiratory chain complex I assembly
  evidence_type: IMP
  original_reference_id: PMID:30140060
  qualifier: involved_in
  review:
    summary: Experimental (IMP) annotation to Complex I assembly. NDUFS3 patient variants reduced NDUFS3
      protein levels and impaired Complex I assembly in patient-derived cells, consistent with NDUFS3
      acting as an early nucleation point of the peripheral arm (PMID:17209039).
    action: ACCEPT
    reason: Core biological process. NDUFS3 is required for correct stepwise assembly of Complex I; its
      loss impairs assembly.
    supported_by:
    - reference_id: PMID:30140060
      supporting_text: decreased amount of NDUFS3 and complex I assembly when compared with two control
        cells
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31536960
  qualifier: enables
  review:
    summary: Curated protein binding IPI capturing the NDUFS3-RAB5IF interaction. While this is a genuine
      curated interaction, the bare protein binding term itself is uninformative as a molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per curation guidelines protein binding is not retained as an informative function. The interaction
      is noted, but conveys no specific molecular activity.
    supported_by:
    - reference_id: PMID:31536960
      supporting_text: Regulators of the Respirasome and Neurogenesis
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-163217
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to the mitochondrial matrix, from the reaction in which Complex I
      oxidizes NADH and reduces CoQ. NDUFS3 is a matrix-side peripheral-arm subunit, so the matrix location
      is compatible, though the primary curated anatomical location is the inner membrane (GO:0005743).
    action: KEEP_AS_NON_CORE
    reason: Compatible with NDUFS3's matrix-facing topology but less precise than the inner-membrane annotation;
      retained as non-core localization context.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799178
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to the mitochondrial matrix from a Complex I biogenesis reaction
      (Intermediate 1 binds HP subcomplex to form Intermediate 2).
    action: KEEP_AS_NON_CORE
    reason: Assembly-intermediate localization context; compatible with matrix-side topology but less
      precise than GO:0005743.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799179
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to the mitochondrial matrix from a Complex I biogenesis reaction
      (peripheral arm subunits bind the 815 kDa complex).
    action: KEEP_AS_NON_CORE
    reason: Assembly-intermediate localization context; less precise than GO:0005743.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799191
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to the mitochondrial matrix from a Complex I biogenesis reaction
      (Intermediate 2 binds MT-ND1:NDUFAF5:NDUFAF6).
    action: KEEP_AS_NON_CORE
    reason: Assembly-intermediate localization context; less precise than GO:0005743.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799196
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to the mitochondrial matrix from a Complex I biogenesis reaction
      (dissociation of assembly factors to form Complex I).
    action: KEEP_AS_NON_CORE
    reason: Assembly-intermediate localization context; less precise than GO:0005743.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799197
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to the mitochondrial matrix from a Complex I biogenesis reaction
      (ND4, ND5 bind the 550 kDa complex).
    action: KEEP_AS_NON_CORE
    reason: Assembly-intermediate localization context; less precise than GO:0005743.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799202
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to the mitochondrial matrix from a Complex I biogenesis reaction
      (315 kDa binds 370 kDa to form 550 kDa complex).
    action: KEEP_AS_NON_CORE
    reason: Assembly-intermediate localization context; less precise than GO:0005743.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799203
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to the mitochondrial matrix from a Complex I biogenesis reaction
      (IP subcomplex binds NDUFAF3, NDUFAF4, TIMMDC1). NDUFS3 is part of the IP subcomplex referenced
      here.
    action: KEEP_AS_NON_CORE
    reason: Assembly-intermediate localization context; less precise than GO:0005743.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800868
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to the mitochondrial matrix from the reaction forming the IP subcomplex,
      of which NDUFS3 is a component.
    action: KEEP_AS_NON_CORE
    reason: Assembly-intermediate localization context; less precise than GO:0005743.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838035
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to the mitochondrial matrix from a mitochondrial protein quality-control
      reaction (CLPXP binds matrix proteins). This reflects NDUFS3 as a potential CLPXP substrate rather
      than a Complex I function.
    action: KEEP_AS_NON_CORE
    reason: Localization is compatible but the reaction is a generic matrix quality-control context, not
      a core NDUFS3 function.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838289
  qualifier: located_in
  review:
    summary: Reactome TAS annotation to the mitochondrial matrix from a mitochondrial protein quality-control
      reaction (CLPXP degrades matrix proteins).
    action: KEEP_AS_NON_CORE
    reason: Generic matrix quality-control context, not a core NDUFS3 function; localization is compatible.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19822128
  qualifier: enables
  review:
    summary: protein binding IPI from the study showing DJ-1 (PARK7) binds Complex I and maintains its
      activity. The bare protein binding term is uninformative as a molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per curation guidelines protein binding is not retained. Note the study primarily demonstrated
      DJ-1 binding to NDUFA4 and ND1, not directly to NDUFS3.
    supported_by:
    - reference_id: PMID:19822128
      supporting_text: DJ-1 directly bound to NDUFA4 and ND1
- term:
    id: GO:0021762
    label: substantia nigra development
  evidence_type: HEP
  original_reference_id: PMID:22926577
  qualifier: involved_in
  review:
    summary: HEP (inferred from high-throughput expression) annotation to substantia nigra development,
      from a differential proteomics survey of human substantia nigra in neurodegenerative disease. This
      reflects differential NDUFS3 expression/abundance, not a role in the development of the substantia
      nigra.
    action: MARK_AS_OVER_ANNOTATED
    reason: The evidence is a differential-abundance proteomics comparison in disease tissue; it does
      not establish a developmental function for NDUFS3. This is an over-annotation driven by expression
      detection in substantia nigra.
    supported_by:
    - reference_id: PMID:22926577
      supporting_text: Using a quantitative proteomic approach, we investigated protein expressions in
        the substantia nigra
- term:
    id: GO:0072593
    label: reactive oxygen species metabolic process
  evidence_type: IMP
  original_reference_id: PMID:16826196
  qualifier: involved_in
  review:
    summary: Experimental (IMP) annotation to reactive oxygen species metabolic process. siRNA knockdown
      of NDUFS3 in cancer cell lines reduced ROS production and conferred resistance to IFN-beta/RA-induced
      apoptosis. This is a downstream physiological consequence of reduced Complex I function rather than
      a core molecular role of NDUFS3.
    action: KEEP_AS_NON_CORE
    reason: Reduced ROS on NDUFS3 knockdown reflects loss of Complex I activity (a known ROS source),
      a secondary/downstream effect. Retained as a non-core process.
    supported_by:
    - reference_id: PMID:16826196
      supporting_text: two subunits of MRC complex I, by siRNA in two cancer cell lines conferred resistance
        to IFN-beta/RA-induced apoptosis and reduced ROS production
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19463981
  qualifier: enables
  review:
    summary: Curated protein binding IPI capturing the interaction between NDUFS3 and the Complex I assembly
      factor NDUFAF3. Although a genuine, biologically meaningful interaction, the bare protein binding
      term itself conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per curation guidelines protein binding is not retained as a function. The assembly-factor
      interaction is relevant context for GO:0032981 (Complex I assembly).
    supported_by:
    - reference_id: PMID:19463981
      supporting_text: NDUFAF3 is a genuine mitochondrial complex I assembly protein that interacts with
        complex I subunits
- term:
    id: GO:0003954
    label: NADH dehydrogenase activity
  evidence_type: IMP
  original_reference_id: PMID:16826196
  qualifier: enables
  review:
    summary: Experimental (IMP) annotation to the broader NADH dehydrogenase activity, from the NDUFS3
      siRNA-knockdown study affecting Complex I function. This is a looser parent of the specific NADH
      dehydrogenase (ubiquinone) activity and, like the specific term, is a complex-level activity NDUFS3
      contributes to rather than independently enables.
    action: MARK_AS_OVER_ANNOTATED
    reason: Broader/looser than the specific GO:0008137 already captured with contributes_to, and framed
      as enables for a cofactor-less structural subunit. The specific complex-level term is preferred.
    supported_by:
    - reference_id: PMID:16826196
      supporting_text: NDUFS3 (NADH dehydrogenase (ubiquinone) Fe-S protein 3), two subunits of MRC complex
        I
- term:
    id: GO:0003954
    label: NADH dehydrogenase activity
  evidence_type: IMP
  original_reference_id: PMID:11112787
  qualifier: enables
  review:
    summary: Experimental (IMP) annotation to NADH dehydrogenase activity from a monoclonal antibody study
      of Complex I subunit assembly patterns (the 30 kDa subunit is NDUFS3). A broad complex-level activity
      term framed with enables.
    action: MARK_AS_OVER_ANNOTATED
    reason: Broader than the specific GO:0008137 captured as contributes_to; the activity is a complex-level
      property, not independently enabled by NDUFS3.
    supported_by:
    - reference_id: PMID:11112787
      supporting_text: a new set of monoclonal antibodies that react with 39-, 30-, 20-, 18-, 15-, and
        8-kDa subunits of Complex I
- term:
    id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  evidence_type: NAS
  original_reference_id: PMID:9878551
  qualifier: involved_in
  review:
    summary: Author-statement (NAS) annotation to the core Complex I biological process, from the cDNA
      characterization paper describing Complex I's main function as transport of electrons from NADH
      to ubiquinone.
    action: ACCEPT
    reason: Correct core BP; redundant with the experimental IMP annotations.
    supported_by:
    - reference_id: PMID:9878551
      supporting_text: Its main function is the transport of electrons from NADH to ubiquinone
- term:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  evidence_type: NAS
  original_reference_id: PMID:9878551
  qualifier: enables
  review:
    summary: Author-statement (NAS) annotation of the complex-level NADH dehydrogenase (ubiquinone) activity
      with enables, from the cDNA characterization paper.
    action: MODIFY
    reason: The activity is a property of the assembled complex; contributes_to is more accurate for this
      cofactor-less core subunit than enables. Retain term with contributes_to.
    proposed_replacement_terms:
    - id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    supported_by:
    - reference_id: PMID:9878551
      supporting_text: NADH:ubiquinone oxidoreductase (complex I)
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: NAS
  original_reference_id: PMID:9647766
  qualifier: located_in
  review:
    summary: Author-statement (NAS) mitochondrial localization from the cDNA cloning of the human IP-fraction
      Complex I subunits including NDUFS3 (30 kDa).
    action: ACCEPT
    reason: Correct general localization, consistent with all other evidence.
    supported_by:
    - reference_id: PMID:9647766
      supporting_text: NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial respiratory chain
- term:
    id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  evidence_type: NAS
  original_reference_id: PMID:9647766
  qualifier: involved_in
  review:
    summary: Author-statement (NAS) annotation to the core Complex I biological process, from the cDNA
      cloning paper of the IP-fraction subunits.
    action: ACCEPT
    reason: Correct core BP; redundant with experimental IMP annotations.
    supported_by:
    - reference_id: PMID:9647766
      supporting_text: NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial respiratory chain
- term:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  evidence_type: NAS
  original_reference_id: PMID:9647766
  qualifier: enables
  review:
    summary: Author-statement (NAS) annotation of the complex-level NADH dehydrogenase (ubiquinone) activity
      with enables, from the IP-fraction cDNA cloning paper.
    action: MODIFY
    reason: Complex-level activity; contributes_to is more accurate than enables for this cofactor-less
      structural subunit. Retain term with contributes_to.
    proposed_replacement_terms:
    - id: GO:0008137
      label: NADH dehydrogenase (ubiquinone) activity
    supported_by:
    - reference_id: PMID:9647766
      supporting_text: important prosthetic groups highly conserved among species
- term:
    id: GO:0009055
    label: electron transfer activity
  evidence_type: NAS
  original_reference_id: PMID:9647766
  qualifier: enables
  review:
    summary: Author-statement (NAS) annotation to electron transfer activity. In Complex I, the electron-transfer
      chemistry is carried out by the flavin (in NDUFV1) and the chain of iron-sulfur clusters (in NDUFV1/NDUFV2/NDUFS1/NDUFS7/NDUFS8
      etc.). NDUFS3, despite its historical "iron-sulfur protein 3" name, carries no redox cofactor and
      does not itself transfer electrons.
    action: MARK_AS_OVER_ANNOTATED
    reason: NDUFS3 is a cofactor-less structural core subunit; it does not carry a redox center and does
      not itself have electron transfer activity. Assigning this MF to NDUFS3 is an over-annotation stemming
      from the misleading "IP/iron-sulfur protein" naming.
    supported_by:
    - reference_id: PMID:9647766
      supporting_text: it contains important prosthetic groups highly conserved among species
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IDA
  original_reference_id: PMID:17209039
  qualifier: located_in
  review:
    summary: Experimental (IDA) annotation to the mitochondrial membrane, from the tagged-NDUFS3 assembly-tracing
      study. Consistent with, but less specific than, the inner-membrane annotation.
    action: ACCEPT
    reason: Correct, if general, membrane localization; subsumed by the more specific GO:0005743.
    supported_by:
    - reference_id: PMID:17209039
      supporting_text: the entry point of mitochondrial subunits
- term:
    id: GO:0005198
    label: structural molecule activity
  evidence_type: IMP
  original_reference_id: PMID:30140060
  qualifier: enables
  review:
    summary: Proposed subunit-specific molecular function. NDUFS3 is a cofactor-less core structural
      subunit of the Complex I peripheral (Q-module) arm; its own molecular role is to provide a
      structural scaffold required for holoenzyme assembly and catalysis, rather than to independently
      carry out the complex-level NADH:ubiquinone oxidoreductase reaction. This captures the
      structural-constituent role that underlies the contributes_to GO:0008137 annotation.
    action: NEW
    reason: NDUFS3 loss-of-function reduces both Complex I assembly and activity, consistent with a
      structural constituent role. Added to reflect the subunit-specific MF paired with the
      complex-level contributes_to GO:0008137 activity in core_functions.
    supported_by:
    - reference_id: PMID:30140060
      supporting_text: decreased amount of NDUFS3 and complex I assembly when compared with two control cells
    - reference_id: file:human/NDUFS3/NDUFS3-uniprot.txt
      supporting_text: catalytic activity and assembly of complex I
core_functions:
- description: Structural core subunit of the Q-module of the Complex I peripheral arm that contributes
    to the complex-level NADH:ubiquinone oxidoreductase (NADH dehydrogenase (ubiquinone)) catalytic activity.
    NDUFS3 carries no redox cofactor of its own; it provides an essential structural scaffold required
    for the holoenzyme's activity.
  molecular_function:
    id: GO:0005198
    label: structural molecule activity
  contributes_to_molecular_function:
    id: GO:0008137
    label: NADH dehydrogenase (ubiquinone) activity
  directly_involved_in:
  - id: GO:0006120
    label: mitochondrial electron transport, NADH to ubiquinone
  - id: GO:0032981
    label: mitochondrial respiratory chain complex I assembly
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  in_complex:
    id: GO:0045271
    label: respiratory chain complex I
  supported_by:
  - reference_id: file:human/NDUFS3/NDUFS3-uniprot.txt
    supporting_text: catalytic activity and assembly of complex I
  - reference_id: PMID:30140060
    supporting_text: decreased amount of NDUFS3 and complex I assembly when compared with two control
      cells
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/NDUFS3/NDUFS3-uniprot.txt
  title: UniProt entry O75489 (NDUS3_HUMAN)
  findings: []
- id: PMID:11112787
  title: Human complex I defects can be resolved by monoclonal antibody analysis into distinct subunit
    assembly patterns.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. Monoclonal antibody study of Complex I subunits (including the 30 kDa
      NDUFS3); supports subunit/assembly context but the NADH dehydrogenase activity annotation is a complex-level
      property, not independently enabled by NDUFS3.
- id: PMID:12611891
  title: The subunit composition of the human NADH dehydrogenase obtained by rapid one-step immunopurification.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Immunopurification + MS identification of human Complex I subunit composition;
      directly supports NDUFS3 Complex I membership and inner-membrane localization.
- id: PMID:14729820
  title: Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. First report that NDUFS3 mutations (the seventh/last complex I core
      subunit) cause Leigh syndrome and complex I deficiency; anchors the core function/BP/disease annotations.
- id: PMID:15250827
  title: 'Structural organization of mitochondrial human complex I: role of the ND4 and ND5 mitochondria-encoded
    subunits and interaction with prohibitin.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Source of a bare protein binding IPI; focused on ND4/ND5 and prohibitin,
      contributes no specific NDUFS3 molecular function.
- id: PMID:16826196
  title: 'Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex
    I in the interferon-beta and retinoic acid-induced cancer cell death.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. NDUFS3 siRNA knockdown reduced ROS and apoptosis; supports a downstream
      ROS-metabolic (non-core) role, not a core molecular function.
- id: PMID:17209039
  title: Identification of mitochondrial complex I assembly intermediates by tracing tagged NDUFS3 demonstrates
    the entry point of mitochondrial subunits.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Tagged-NDUFS3 tracing established Complex I assembly intermediates
      and the entry point of mtDNA-encoded subunits; supports membership, assembly, and membrane localization.
- id: PMID:18826940
  title: Subunits of mitochondrial complex I exist as part of matrix- and membrane-associated subcomplexes
    in living cells.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Live-cell FRAP of GFP-tagged NDUFS3; supports inner-membrane (matrix-side)
      localization and existence of a matrix-soluble NDUFS3 subassembly.
- id: PMID:19463981
  title: Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly
    protein, cause fatal neonatal mitochondrial disease.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. Establishes NDUFAF3 as a Complex I assembly factor interacting with
      Complex I subunits (incl. NDUFS3); relevant to assembly context, source of a bare protein binding
      IPI.
- id: PMID:19688755
  title: LC-MS/MS as an alternative for SDS-PAGE in blue native analysis of protein complexes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Methods paper; source of a bare protein binding IPI with no specific
      NDUFS3 function.
- id: PMID:19822128
  title: DJ-1 binds to mitochondrial complex I and maintains its activity.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. DJ-1 was shown to bind NDUFA4 and ND1 (not directly NDUFS3); source
      of a bare, uninformative protein binding IPI.
- id: PMID:21310150
  title: NDUFB7 and NDUFA8 are located at the intermembrane surface of complex I.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Focused on NDUFB7/NDUFA8 topology; source of a bare protein binding
      IPI with no specific NDUFS3 function.
- id: PMID:22926577
  title: Quantitative proteomic analysis of human substantia nigra in Alzheimer's disease, Huntington's
    disease and Multiple sclerosis.
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: PubMed-verified identifier, but the paper is a differential-abundance proteomics survey;
      it does not support a role for NDUFS3 in substantia nigra development. The HEP substantia nigra
      development annotation is an over-annotation.
- id: PMID:24344204
  title: TIMMDC1/C3orf1 functions as a membrane-embedded mitochondrial complex I assembly factor through
    association with the MCIA complex.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Establishes TIMMDC1 as a Complex I assembly factor; source of a bare
      protein binding IPI, assembly context relevant but no specific NDUFS3 MF.
- id: PMID:27499296
  title: Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. High-throughput mitochondrial interaction mapping; source of bare protein
      binding IPIs.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Large-scale interactome; source of bare protein binding IPIs.
- id: PMID:28844695
  title: Architecture of Human Mitochondrial Respiratory Megacomplex I(2)III(2)IV(2).
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Cryo-EM of the human respiratory megacomplex resolving individual Complex
      I subunits; supports NDUFS3 Complex I membership and inner-membrane localization.
- id: PMID:30030361
  title: Assembly of mammalian oxidative phosphorylation complexes I-V and supercomplexes.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified review of OXPHOS complex assembly; supports the (non-core) complex-level
      aerobic respiration / ATP-synthesis process annotations.
- id: PMID:30140060
  title: A Novel NDUFS3 mutation in a Chinese patient with severe Leigh syndrome.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Second NDUFS3 Leigh syndrome report; patient variants reduced NDUFS3
      levels and Complex I assembly, anchoring the contributes_to catalytic-activity, electron-transport,
      and assembly annotations.
- id: PMID:31536960
  title: Rewiring of the Human Mitochondrial Interactome during Neuronal Reprogramming Reveals Regulators
    of the Respirasome and Neurogenesis.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. Mitochondrial interactome study; identified NDUFS3-RAB5IF interaction
      and supports Complex I membership; source of a bare protein binding IPI.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. HuRI Y2H reference map; source of bare protein binding IPIs.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread
    Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Neurodegeneration interactome; source of bare protein binding IPIs.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. BioPlex proteome-scale interactome; source of bare protein binding
      IPIs.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. High-confidence human mitochondrial proteome; supports NDUFS3 as a
      bona fide mitochondrial protein (HTP localization).
- id: PMID:9647766
  title: 'cDNA sequence and chromosomal localization of the remaining three human nuclear encoded iron
    sulphur protein (IP) subunits of complex I: the human IP fraction is completed.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. cDNA cloning of NDUFS2/NDUFS3/NDUFS6; supports mitochondrial localization
      and Complex I membership. NDUFS3 itself carries no Fe-S cluster despite the iron-sulphur-protein
      fraction name (basis for over-annotating electron transfer activity).
- id: PMID:9878551
  title: 'cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase: human complex I cDNA
    characterization completed.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. Completes the human Complex I cDNA characterization; describes the
      complex's core NADH-to-ubiquinone electron transport and proton translocation.
- id: Reactome:R-HSA-163217
  title: Complex I oxidises NADH to NAD+, reduces CoQ to CoQH2
  findings: []
- id: Reactome:R-HSA-6799178
  title: Intermediate 1 binds HP subcomplex to form Intermediate 2
  findings: []
- id: Reactome:R-HSA-6799179
  title: Peripheral arm subunits bind the 815kDa complex to form a 980kDa complex
  findings: []
- id: Reactome:R-HSA-6799191
  title: Intermediate 2 binds MT-ND1:NDUFAF5:NDUFAF6 to form a 315kDa subcomplex
  findings: []
- id: Reactome:R-HSA-6799196
  title: The MCIA complex, NDUFAF2-7 all dissociate from the 980kDa complex, resulting in Complex I
  findings: []
- id: Reactome:R-HSA-6799197
  title: ND4, ND5 bind the 550kDa complex to form the 815kDa complex
  findings: []
- id: Reactome:R-HSA-6799202
  title: The 315kDa subcomplex binds the 370kDa subcomplex to form the 550kDa complex
  findings: []
- id: Reactome:R-HSA-6799203
  title: IP subcomplex binds NDUFAF3, NDUFAF4, TIMMDC1 to form Intermediate 1
  findings: []
- id: Reactome:R-HSA-6800868
  title: NDUF subunits bind to form the IP subcomplex
  findings: []
- id: Reactome:R-HSA-9838035
  title: CLPXP binds mitochondrial matrix proteins
  findings: []
- id: Reactome:R-HSA-9838289
  title: CLPXP degrades mitochondrial matrix proteins
  findings: []

Gene Description

Existing Annotations Review

Core Functions

References

📚 Additional Documentation

Notes

NDUFS3 (O75489) review notes

Identity

Verified biology

Localization / topology

Assembly / entry point

Molecular function annotations

protein binding (GO:0005515) IPIs

Other BP

Core functions

📄 View Raw YAML