NDUFV1 encodes the 51 kDa flavoprotein subunit of mitochondrial NADH:ubiquinone oxidoreductase (Complex I, EC 7.1.1.2). It is a core catalytic subunit located in the N-module at the matrix-facing tip of the peripheral (hydrophilic) arm. NDUFV1 contains the FMN cofactor that serves as the primary electron acceptor from NADH, initiating electron transfer through a chain of iron-sulfur clusters toward ubiquinone. NDUFV1 also harbors one [4Fe-4S] cluster (N3) that participates in the electron relay. The reduced FMN site is also the predominant source of reactive oxygen species (superoxide/H2O2) produced by Complex I. NDUFV1 is part of the flavoprotein (FP) subcomplex together with NDUFV2 and NDUFV3. Biallelic mutations in NDUFV1 cause mitochondrial Complex I deficiency, nuclear type 4 (MC1DN4), typically presenting as Leigh syndrome with leukodystrophy, myoclonic epilepsy, and progressive neurodegeneration.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0045271 respiratory chain complex I | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation that NDUFV1 is part of respiratory chain complex I. This is a core structural annotation. NDUFV1 is one of the 45 subunits of mammalian Complex I, specifically located in the flavoprotein (FP) subcomplex of the N-module at the tip of the peripheral arm (PMID:28844695, PMID:12611891). The cryo-EM structure of the human respiratory megacomplex directly resolved NDUFV1 within Complex I (PMID:28844695). The phylogenetic inference is well-supported by multiple lines of evidence. Reason: NDUFV1 is unambiguously a core subunit of Complex I. Confirmed by cryo-EM structure (PMID:28844695), immunopurification and mass spectrometry (PMID:12611891), and monoclonal antibody analysis (PMID:11112787). This is a core annotation. Supporting Evidence: PMID:28844695 The MCI2III2IV2 forms a circular structure with the dimeric CIII located in the center, where it is surrounded by two copies each of CI and CIV PMID:12611891 we can resolve and identify the human homologues of 42 polypeptides detected so far in the more extensively studied beef heart complex I |
| GO:0006120 mitochondrial electron transport, NADH to ubiquinone | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for the specific biological process of electron transport from NADH to ubiquinone in mitochondria. NDUFV1 is the entry point for this process: NADH donates electrons to FMN bound in NDUFV1, and then electrons pass along a chain of iron-sulfur clusters to the terminal acceptor ubiquinone (PMID:28844695). The deep research review confirms NDUFV1's FMN cofactor is the initial electron acceptor (file:human/NDUFV1/NDUFV1-deep-research-falcon.md). Reason: This is the defining biological process for NDUFV1 and Complex I. NDUFV1 directly initiates this process by accepting electrons from NADH at its FMN site. The IBA is phylogenetically sound and supported by extensive experimental evidence. Supporting Evidence: PMID:28844695 The respiratory megacomplex represents the highest-order assembly of respiratory chain complexes, and it allows mitochondria to respond to energy-requiring conditions PMID:8288251 plays an important role in the formation of the NADH-binding site and is believed to be the principal site of entry for electrons donated by NADH into the respiratory chain |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: IEA annotation inferred from GO:0008137 (NADH dehydrogenase ubiquinone activity) via logical inference. Complex I couples electron transfer to proton translocation across the inner mitochondrial membrane. However, the proton pumping activity is carried out by the membrane arm of Complex I (the P-module), not by the peripheral arm where NDUFV1 resides. NDUFV1 is in the N-module performing electron transfer, while the proton channels are formed by ND subunits (ND1, ND2, ND4, ND5) in the membrane arm (PMID:30030361). Reason: While Complex I as a whole does perform proton transmembrane transport, NDUFV1 is located in the peripheral arm far from the proton-translocating membrane domain. The annotation is not wrong at the complex level, but it is imprecise when applied to this specific subunit. The proton translocation is mechanistically coupled to electron transfer but performed by a different structural module. Keep as non-core. |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for inner membrane localization via combined automated methods. NDUFV1 is part of Complex I which is embedded in the inner mitochondrial membrane. However, NDUFV1 itself is a peripheral membrane protein facing the matrix, not an integral membrane protein. UniProt indicates matrix-side peripheral localization (by similarity to rat ortholog P25708). The annotation is acceptable as Complex I is an inner membrane complex. Reason: Correct. NDUFV1 is part of Complex I which is located in the mitochondrial inner membrane. NDUFV1 faces the matrix side as a peripheral membrane protein. Supporting Evidence: PMID:28844695 The structure not only reveals the precise assignment of individual subunits of human CI and CIII, but also enables future in-depth analysis of the electron transport chain as a whole |
| GO:0008137 NADH dehydrogenase (ubiquinone) activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for the overall Complex I catalytic activity (NADH + ubiquinone -> NAD+ + ubiquinol + proton translocation). GO:0008137 represents the complete reaction catalyzed by the entire Complex I holoenzyme. NDUFV1 contributes to this activity by providing the NADH oxidation/FMN reduction step, but the full reaction from NADH to ubiquinone involves the entire electron relay chain across multiple subunits plus proton translocation by the membrane arm (PMID:28844695). The qualifier should ideally be 'contributes_to' rather than 'enables' for this complex-level activity, but the IEA is acceptable as a broader computational annotation. Reason: Correct but represents the complex-level reaction. NDUFV1 contributes_to this activity as the NADH-accepting subunit. IEA annotations are acceptable at broader levels. Consistent with IDA annotation from PMID:28844695. |
| GO:0010181 FMN binding | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation for FMN binding from InterPro domain mapping. NDUFV1 contains one FMN (flavin mononucleotide) cofactor that serves as the primary electron acceptor from NADH. The FMN binding is confirmed by the cryo-EM structure (PMID:28844695) and UniProt cofactor annotation. The InterPro domains IPR001949 and IPR011537 support this. Reason: Core molecular function. NDUFV1 binds FMN as a cofactor essential for its catalytic role in NADH oxidation. Confirmed by cryo-EM structure (PMID:28844695) showing FMN bound in the NDUFV1 subunit. UniProt states "Binds 1 FMN" with experimental evidence. Supporting Evidence: PMID:28844695 The respiratory megacomplex represents the highest-order assembly of respiratory chain complexes file:human/NDUFV1/NDUFV1-deep-research-falcon.md NDUFV1 binds FMN as the primary electron acceptor for NADH and harbors canonical motifs that support NADH/FMN and Fe-S relay connectivity at the N-module interface |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for general oxidoreductase activity from UniProtKB keyword mapping (KW-0560: Oxidoreductase). NDUFV1 is part of an oxidoreductase complex and itself catalyzes the oxidation of NADH at its FMN site. This is a correct but very broad parent term. More specific child terms (GO:0008137, GO:0003954) are more informative. Reason: Correct but very general. NDUFV1 is an oxidoreductase subunit. The more specific GO:0008137 and GO:0003954 are also present or should be present. IEA at this level is acceptable. |
| GO:0022904 respiratory electron transport chain | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for respiratory electron transport chain from UniProt keyword mapping (KW-0679: Respiratory chain). NDUFV1 is part of Complex I, the first enzyme of the mitochondrial respiratory electron transport chain. This is broader than GO:0006120 (mitochondrial electron transport, NADH to ubiquinone) but still correct. Reason: Correct but more general than the IBA annotation GO:0006120. Complex I is the entry point of the respiratory electron transport chain for NADH-derived electrons. Acceptable for IEA to use the broader term. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for metal ion binding from UniProt keyword mapping (KW-0479: Metal-binding). NDUFV1 contains one [4Fe-4S] cluster (cluster N3) with iron atoms coordinated by Cys379, Cys382, Cys385, and Cys425 (UniProt feature annotations, PMID:28844695). The iron in the Fe-S cluster constitutes metal ion binding. This is correct but very broad. The more specific GO:0051539 (4 iron, 4 sulfur cluster binding) is more informative. Reason: Correct but very general. NDUFV1 binds iron via its [4Fe-4S] cluster. The more specific child term GO:0051539 is also annotated. Acceptable for IEA to use the broader term. |
| GO:0051287 NAD binding | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation for NAD binding from InterPro domain mapping (IPR011537). NDUFV1 contains the NADH-binding site where NADH donates its electrons to FMN. UniProt annotates NADH binding at residues 87-96. The term GO:0051287 refers to NAD binding generally. Since NDUFV1 binds NADH (the reduced form) rather than NAD+, this is still correct as GO:0051287 encompasses both oxidized and reduced forms. This is a core function of NDUFV1. Reason: Core molecular function. NDUFV1 is the NADH-binding subunit of Complex I. The NADH binding site is at residues 87-96 (UniProt feature annotation). NADH binding is essential for NDUFV1's catalytic role. Supporting Evidence: PMID:8288251 plays an important role in the formation of the NADH-binding site and is believed to be the principal site of entry for electrons donated by NADH into the respiratory chain |
| GO:0051536 iron-sulfur cluster binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for iron-sulfur cluster binding from UniProt keyword mapping (KW-0411: Iron-sulfur). NDUFV1 contains one [4Fe-4S] cluster (N3). This is a correct but less specific parent of GO:0051539. Both are present in annotations. Reason: Correct. NDUFV1 binds an iron-sulfur cluster. The more specific child term GO:0051539 is also annotated. Both are acceptable. |
| GO:0051539 4 iron, 4 sulfur cluster binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for [4Fe-4S] cluster binding from combined automated methods including InterPro domains IPR001949, IPR011537, IPR019575 and UniProt keyword KW-0004 (4Fe-4S). NDUFV1 binds one [4Fe-4S] cluster (N3) confirmed by the cryo-EM structure at 3.4A resolution (PMID:28844695). The four cysteine ligands are at positions 379, 382, 385, and 425 as shown in PDB structures 5XTB/5XTD/5XTH. Reason: Core cofactor binding annotation. The [4Fe-4S] cluster N3 is essential for the electron relay from FMN toward the downstream Fe-S clusters in NDUFS1. Confirmed by cryo-EM structure (PMID:28844695) and UniProt binding site annotations. Supporting Evidence: PMID:28844695 The structure not only reveals the precise assignment of individual subunits of human CI and CIII, but also enables future in-depth analysis of the electron transport chain as a whole file:human/NDUFV1/NDUFV1-deep-research-falcon.md Electrons flow NADH to FMN (bound in NDUFV1) to series of Fe-S clusters to terminal cluster N2 near the ubiquinone site |
| GO:0005515 protein binding | IPI PMID:24344204 TIMMDC1/C3orf1 functions as a membrane-embedded mitochondria... | KEEP AS NON CORE | Summary: IPI annotation for interaction with NDUFV3 (P56181) from Guarani et al. (2014), who used interaction proteomics to interrogate molecular associations of Complex I subunits and assembly factors. NDUFV3 is a fellow subunit of the FP subcomplex within the N-module, so the NDUFV1-NDUFV3 interaction is expected and biologically meaningful as intra-complex subunit interaction during Complex I assembly. Reason: The NDUFV1-NDUFV3 interaction is biologically meaningful as both are subunits of the FP subcomplex. However, 'protein binding' is uninformative as a GO term and the subunit interaction is already captured by the CC annotation GO:0045271 (part_of respiratory chain complex I). |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | KEEP AS NON CORE | Summary: IPI annotation for interaction with NDUFV3 (P56181) from Fasci et al. (2018), a crosslinking mass spectrometry study in intact cell nuclei focused on histone interactions. This is a large-scale crosslinking study. The detection of NDUFV1-NDUFV3 crosslinks likely reflects their close physical proximity within the FP subcomplex. Reason: The NDUFV1-NDUFV3 interaction reflects intra-complex proximity within the FP subcomplex. The GO term 'protein binding' is uninformative and the interaction is already captured by Complex I membership. Keep as non-core. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: IPI annotation for interaction with CYSRT1 (A8MQ03) from Luck et al. (2020), a reference map of the human binary protein interactome. CYSRT1 is a small cysteine-rich protein of unknown function. The biological significance of an NDUFV1-CYSRT1 interaction is unclear and likely represents a non-specific or indirect detection from this high-throughput screen. CYSRT1 is a keratinocyte-associated cytoplasmic protein with no reported mitochondrial role, and a Y2H-format binary assay places both partners outside their native compartments, so the pairing carries no functional implication for a matrix-facing Complex I subunit. Reason: Unlike the NDUFV3 and RAB5IF interactions, which reflect genuine Complex I neighbourhood and assembly biology, the CYSRT1 pairing is an isolated binary interactome hit with no supporting biology and no compartment overlap. Combined with the uninformativeness of bare 'protein binding' (GO:0005515), this is best flagged as an over-annotation rather than merely demoted to non-core. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: IPI annotations for multiple interactors from Haenig et al. (2020), an interactome mapping study focused on neurodegenerative disease proteins. The GOA contains many individual IPI lines from this PMID with various interactors including PRKCA, PSMB1, PSMA3, MNDA, VDAC2, COPS2, YWHAG, SETDB1, PSMD5, SMU1, FBXO42, RBBP6, FAM9A, LMO3, FBXO25, TBC1D22A, USP25, OPTN, SPAG8, RMND5A, RNF146, ARFGAP3, BTRC, KAT5, and Q9NTX7. This is a large-scale Y2H-based interactome study. Many of these interactions are of unclear biological significance for a mitochondrial matrix-facing Complex I subunit. Some may represent protein aggregation artifacts, as the study specifically examined protein aggregation in neurodegeneration. Reason: Systematic yeast two-hybrid screening detects pairings in the yeast nucleus/cytosol, a setting in which a mitochondrial matrix-facing Complex I subunit is not normally present; the study itself was designed around protein aggregation in neurodegeneration, which favours sticky, compartment-agnostic hits. With ~25 unrelated partners reported for NDUFV1 from a single screen and no orthogonal validation for any of them, these lines over-state what is known about NDUFV1 binding rather than adding non-core biology, and bare 'protein binding' (GO:0005515) is uninformative in any case. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: IPI annotation for interaction with NDUFV3 (P56181) from Huttlin et al. (2021), a dual proteome-scale network study. This again detects the NDUFV1-NDUFV3 interaction, consistent with both being subunits of the FP subcomplex in Complex I. Reason: Confirms the NDUFV1-NDUFV3 intra-complex interaction. Biologically meaningful but 'protein binding' is uninformative and already captured by Complex I membership. |
| GO:0006120 mitochondrial electron transport, NADH to ubiquinone | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for the same process as the IBA above, from combined automated methods (mouse ortholog Q91YT0, Ensembl Compara). Redundant with the IBA but consistent. Reason: Consistent with the IBA annotation. Duplicates are expected when multiple evidence sources converge on the same annotation. |
| GO:0045271 respiratory chain complex I | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for the same CC term as the IBA above, from combined automated methods (mouse ortholog Q91YT0, Ensembl Compara). Redundant with the IBA but consistent. Reason: Consistent with the IBA and multiple IDA/IMP annotations for this term. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: IDA annotation from ComplexPortal based on Guo et al. (2017), who determined the cryo-EM structure of the human respiratory megacomplex I2III2IV2 at 3.4A resolution. The structure directly visualizes NDUFV1 (residues 27-457) within Complex I, which is embedded in the inner mitochondrial membrane. Reason: Direct experimental evidence from cryo-EM structure showing NDUFV1 as part of Complex I in the inner mitochondrial membrane. NDUFV1 is a peripheral membrane protein on the matrix side. Supporting Evidence: PMID:28844695 The structure not only reveals the precise assignment of individual subunits of human CI and CIII, but also enables future in-depth analysis of the electron transport chain as a whole |
| GO:0009060 aerobic respiration | NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-... | KEEP AS NON CORE | Summary: NAS annotation from ComplexPortal based on Signes and Fernandez-Vizarra (2018), a review of OXPHOS complex assembly. Complex I is a central component of aerobic respiration, coupling NADH oxidation to the electron transport chain and proton pumping that drives ATP synthesis. NDUFV1 participates in aerobic respiration as the NADH-accepting subunit of Complex I. Reason: Correct but broad. Aerobic respiration encompasses the entire oxidative phosphorylation system. NDUFV1's specific involvement is better captured by GO:0006120 (mitochondrial electron transport, NADH to ubiquinone). Keep as non-core since aerobic respiration is a higher-level process. |
| GO:0042776 proton motive force-driven mitochondrial ATP synthesis | NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-... | KEEP AS NON CORE | Summary: NAS annotation from ComplexPortal suggesting NDUFV1 is involved in proton motive force-driven mitochondrial ATP synthesis. Complex I contributes to ATP synthesis by generating part of the proton motive force through proton pumping. However, NDUFV1 is in the peripheral arm (N-module) performing electron transfer, not in the membrane arm that performs proton translocation. Unlike Complex II (which does not pump protons at all), Complex I does pump protons, so NDUFV1 indirectly contributes to PMF generation. But the annotation is imprecise for this specific subunit. The SDHA review correctly removed the equivalent annotation for SDHA/Complex II because Complex II does not pump protons. For NDUFV1/Complex I, the situation is different since Complex I does pump protons, but NDUFV1's electron transfer role is mechanistically separated from the proton pumping in the membrane arm. Reason: Complex I as a whole contributes to the proton motive force and thus ATP synthesis, but NDUFV1 specifically performs electron transfer in the N-module peripheral arm, not proton translocation. The annotation is not wrong at the complex level, but it is imprecise for this subunit. Keep as non-core since NDUFV1's direct role is electron transfer, with proton pumping being a mechanistically coupled but structurally distinct function of the membrane arm. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: HTP annotation for mitochondrial localization from Morgenstern et al. (2021), a quantitative high-confidence human mitochondrial proteome study. NDUFV1 was identified in the mitochondrial proteome by mass spectrometry. Reason: Correct. NDUFV1 is a well-established mitochondrial protein confirmed by proteomics and structural biology. |
| GO:0045271 respiratory chain complex I | IMP PMID:11112787 Human complex I defects can be resolved by monoclonal antibo... | ACCEPT | Summary: IMP annotation from Triepels et al. (2001), who used monoclonal antibodies and sucrose gradient studies to resolve Complex I defects into distinct subunit assembly patterns. The study examined patients with NDUFV1 defects and showed that mutations in NDUFV1 affect Complex I assembly. The IMP evidence code is appropriate because the mutant phenotype (defective Complex I assembly) demonstrates that NDUFV1 is part of Complex I. Reason: Valid IMP evidence. Mutations in NDUFV1 cause Complex I assembly defects, demonstrating that NDUFV1 is required for and part of Complex I. Supporting Evidence: PMID:11112787 the other patients had defects in NDUFV1, NDUFS2 (two patients), NDUFS4 (two patients), NDUFS7, and NDUFS8 |
| GO:0045271 respiratory chain complex I | IDA PMID:12611891 The subunit composition of the human NADH dehydrogenase obta... | ACCEPT | Summary: IDA annotation from Murray et al. (2003), who determined the subunit composition of human NADH dehydrogenase by rapid one-step immunopurification. NDUFV1 was directly identified as a Complex I subunit by mass spectrometry (MALDI-TOF and LC-MS/MS) of immunoisolated Complex I. Reason: Direct experimental identification of NDUFV1 as a Complex I subunit by immunopurification and mass spectrometry. Supporting Evidence: PMID:12611891 we can resolve and identify the human homologues of 42 polypeptides detected so far in the more extensively studied beef heart complex I |
| GO:0045271 respiratory chain complex I | IMP PMID:24746669 Cyclin B1/Cdk1 coordinates mitochondrial respiration for cel... | ACCEPT | Summary: IMP annotation from Wang et al. (2014), who showed that cyclin B1/Cdk1 phosphorylates Complex I subunits including NDUFV1 to enhance CI activity during G2/M cell cycle progression. The study demonstrates that deficiency of phosphorylation in CI subunits results in impairment of CI function, supporting NDUFV1 as a functional component of Complex I. Reason: Valid IMP evidence. Phosphorylation of NDUFV1 by cyclin B1/Cdk1 enhances Complex I activity, and deficiency of phosphorylation impairs CI function, confirming NDUFV1 is a functional component of Complex I. Supporting Evidence: PMID:24746669 Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function |
| GO:0045271 respiratory chain complex I | IDA PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: IDA annotation from Guo et al. (2017), the cryo-EM structure of the human respiratory megacomplex. NDUFV1 (residues 27-457) was directly visualized within Complex I at 3.4A resolution (PDB: 5XTB, 5XTD, 5XTH, 5XTI). Reason: Direct structural evidence from cryo-EM showing NDUFV1 as a subunit of Complex I. The strongest possible evidence for complex membership. Supporting Evidence: PMID:28844695 The structure not only reveals the precise assignment of individual subunits of human CI and CIII, but also enables future in-depth analysis of the electron transport chain as a whole |
| GO:0045271 respiratory chain complex I | IDA PMID:31536960 Rewiring of the Human Mitochondrial Interactome during Neuro... | ACCEPT | Summary: IDA annotation from Moutaoufik et al. (2019), who generated mitochondrial interaction maps using mass spectrometry-based co-fractionation. NDUFV1 was identified as part of Complex I by co-fractionation profiling. Reason: Valid experimental evidence from co-fractionation mass spectrometry confirming NDUFV1 in Complex I. Supporting Evidence: PMID:31536960 using mass spectrometry-based co-fractionation profiles and phosphoproteomics, we generated mitochondrial interaction maps |
| GO:0006120 mitochondrial electron transport, NADH to ubiquinone | IDA PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: IDA annotation from Guo et al. (2017). The cryo-EM structure of the megacomplex demonstrates the structural basis for electron transport from NADH to ubiquinone, with NDUFV1 containing the FMN cofactor at the entry point. UniProt cites this reference for the catalytic activity (EC 7.1.1.2). Reason: Direct structural evidence supporting NDUFV1's role in electron transport from NADH to ubiquinone. The FMN cofactor in NDUFV1 is the primary electron acceptor from NADH. Supporting Evidence: PMID:28844695 The respiratory megacomplex represents the highest-order assembly of respiratory chain complexes, and it allows mitochondria to respond to energy-requiring conditions |
| GO:0008137 NADH dehydrogenase (ubiquinone) activity | IDA PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: IDA annotation for the complex-level catalytic activity from Guo et al. (2017). The cryo-EM structure reveals NDUFV1 as the FMN-containing subunit where NADH oxidation occurs, contributing to the overall NADH dehydrogenase (ubiquinone) activity of Complex I. GO:0008137 describes the full reaction of the complex (NADH + ubiquinone + protons -> NAD+ + ubiquinol + translocated protons). NDUFV1 contributes to this by catalyzing the NADH oxidation step. Reason: Valid IDA evidence from the structural study. NDUFV1 is the catalytic subunit where NADH is oxidized at the FMN site. The annotation is acceptable as NDUFV1 is the primary functional subunit for this activity, even though the full reaction requires the entire complex. Supporting Evidence: PMID:28844695 The structure not only reveals the precise assignment of individual subunits of human CI and CIII |
| GO:0005515 protein binding | IPI PMID:31536960 Rewiring of the Human Mitochondrial Interactome during Neuro... | KEEP AS NON CORE | Summary: IPI annotation for interaction with RAB5IF (Q9BUV8) from Moutaoufik et al. (2019). UniProt confirms this interaction. RAB5IF is an orphan protein identified as a respirasome assembly factor in this study. The biological significance of the NDUFV1-RAB5IF interaction may relate to Complex I assembly regulation. Reason: The NDUFV1-RAB5IF interaction is biologically interesting given that RAB5IF was identified as a respirasome assembly factor, but 'protein binding' is uninformative as a GO term. Keep as non-core. Supporting Evidence: PMID:31536960 we show the orphan C20orf24 as a respirasome assembly factor whose disruption markedly reduces respiratory chain activity in patients deficient in complex IV |
| GO:0042775 mitochondrial ATP synthesis coupled electron transport | IMP PMID:24746669 Cyclin B1/Cdk1 coordinates mitochondrial respiration for cel... | KEEP AS NON CORE | Summary: IMP annotation from the CAFA annotation challenge, based on Wang et al. (2014). The study showed that cyclin B1/Cdk1 phosphorylation of Complex I subunits enhances CI activity and mitochondrial respiration with enhanced oxygen consumption and ATP generation. Deficiency of phosphorylation impairs CI function and ATP production. The term GO:0042775 encompasses the coupling between electron transport and ATP synthesis in mitochondria. Reason: The annotation is defensible since Complex I electron transport is coupled to ATP synthesis via the proton motive force. However, NDUFV1 specifically performs electron transfer, not ATP synthesis coupling per se. The term is broader than NDUFV1's direct role. Keep as non-core. Supporting Evidence: PMID:24746669 Mitochondria-targeted cyclin B1/Cdk1 increases mitochondrial respiration with enhanced oxygen consumption and ATP generation |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-163217 | ACCEPT | Summary: TAS annotation from Reactome entry R-HSA-163217 (Complex I oxidises NADH to NAD+, reduces CoQ to CoQH2). NDUFV1 is part of Complex I which is embedded in the inner mitochondrial membrane. Reason: Correct localization. Complex I is an inner mitochondrial membrane complex and NDUFV1 is a core subunit. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6788556 | ACCEPT | Summary: TAS annotation from Reactome entry R-HSA-6788556 (NUBPL transfers 4Fe-4S to NDUFV1, V2). This Reactome entry specifically describes the iron-sulfur cluster insertion into NDUFV1 and NDUFV2, placing NDUFV1 at the inner membrane during assembly. Reason: Correct. NUBPL transfers the [4Fe-4S] cluster to NDUFV1 during Complex I assembly at the inner membrane. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799179 | ACCEPT | Summary: TAS annotation from Reactome entry R-HSA-6799179 (Peripheral arm subunits bind the 815kDa complex to form a 980kDa complex). This describes Complex I assembly where peripheral arm subunits including NDUFV1 join the membrane-anchored subcomplex. Reason: Correct. NDUFV1 is assembled into Complex I at the inner membrane. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799196 | ACCEPT | Summary: TAS annotation from Reactome entry R-HSA-6799196 (The MCIA complex, NDUFAF2-7 all dissociate from the 980kDa complex, resulting in Complex I). This describes the final maturation step of Complex I at the inner membrane. Reason: Correct. The final Complex I maturation step occurs at the inner membrane. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6800870 | ACCEPT | Summary: TAS annotation from Reactome entry R-HSA-6800870 (NDUF subunits bind to form the FP subcomplex). This describes the assembly of the flavoprotein subcomplex (NDUFV1 + NDUFV2 + NDUFV3) that constitutes the N-module of Complex I. Reason: Correct. NDUFV1 assembles into the FP subcomplex at the inner membrane. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9837978 | ACCEPT | Summary: TAS annotation from Reactome entry R-HSA-9837978 (LONP1 binds mitochondrial inner membrane proteins). This describes the mitochondrial protease LONP1 binding to inner membrane proteins including Complex I subunits for quality control. Reason: Correct localization. NDUFV1 is a target of LONP1 quality control at the inner membrane. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9838004 | ACCEPT | Summary: TAS annotation from Reactome entry R-HSA-9838004 (LONP1 degrades mitochondrial inner membrane proteins). This describes LONP1-mediated degradation of inner membrane proteins including Complex I subunits. Reason: Correct localization. NDUFV1 can be degraded by LONP1 at the inner membrane as part of mitochondrial protein quality control. |
| GO:0005743 mitochondrial inner membrane | NAS PMID:8288251 Chromosomal localization of the human gene encoding the 51-k... | ACCEPT | Summary: NAS annotation from Ali et al. (1993), who cloned cDNA fragments of the 51-kDa flavoprotein subunit of mitochondrial NADH:ubiquinone oxidoreductase and localized the gene NDUFV1 to chromosome 11q13. The paper describes NDUFV1 as "mitochondrial" and as part of Complex I which resides in the inner membrane. Reason: Correct localization supported by the description of NDUFV1 as a mitochondrial Complex I subunit. Supporting Evidence: PMID:8288251 flavoprotein subunit of mitochondrial NADH:ubiquinone oxidoreductase (Complex I) |
| GO:0006120 mitochondrial electron transport, NADH to ubiquinone | IC PMID:11112787 Human complex I defects can be resolved by monoclonal antibo... | ACCEPT | Summary: IC (Inferred by Curator) annotation from Triepels et al. (2001), with the WITH field referencing GO:0045271 (respiratory chain complex I). The curator inferred that since NDUFV1 is part of Complex I (shown by IMP), it is involved in the electron transport process of Complex I (NADH to ubiquinone). This is a valid curator inference. Reason: Valid curator inference. Since NDUFV1 is part of Complex I and Complex I catalyzes electron transport from NADH to ubiquinone, NDUFV1 is involved in this process. For NDUFV1 specifically, this is a core function as it is the NADH-accepting subunit. Supporting Evidence: PMID:11112787 the other patients had defects in NDUFV1, NDUFS2 (two patients), NDUFS4 (two patients), NDUFS7, and NDUFS8 |
| GO:0008137 NADH dehydrogenase (ubiquinone) activity | NAS PMID:8288251 Chromosomal localization of the human gene encoding the 51-k... | ACCEPT | Summary: NAS annotation from Ali et al. (1993). The paper describes NDUFV1 as "The 51-kDa flavoprotein subunit of mitochondrial NADH:ubiquinone oxidoreductase (Complex I) [NADH dehydrogenase (ubiquinone), flavoprotein 1 (51 kDa); EC 1.6.5.3]" and states it "plays an important role in the formation of the NADH-binding site and is believed to be the principal site of entry for electrons donated by NADH into the respiratory chain." Reason: Valid NAS annotation. The paper clearly describes NDUFV1 as part of the NADH dehydrogenase (ubiquinone) complex and its role in NADH binding. Supporting Evidence: PMID:8288251 NADH dehydrogenase (ubiquinone), flavoprotein 1 (51 kDa); EC 1.6.5.3] plays an important role in the formation of the NADH-binding site and is believed to be the principal site of entry for electrons donated by NADH into the respiratory chain |
| GO:0006120 mitochondrial electron transport, NADH to ubiquinone | NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox... | ACCEPT | Summary: NAS annotation from Loeffen et al. (1998), who completed the cDNA characterization of all nuclear-encoded Complex I subunits. The paper describes Complex I's main function as "the transport of electrons from NADH to ubiquinone, which is accompanied by translocation of protons from the mitochondrial matrix to the intermembrane space." Reason: Valid NAS annotation. The paper clearly describes the function of Complex I in electron transport from NADH to ubiquinone. Supporting Evidence: PMID:9878551 Its main function is the transport of electrons from NADH to ubiquinone, which is accompanied by translocation of protons from the mitochondrial matrix to the intermembrane space |
| GO:0008137 NADH dehydrogenase (ubiquinone) activity | NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox... | ACCEPT | Summary: NAS annotation from Loeffen et al. (1998). The paper describes Complex I as "NADH:ubiquinone oxidoreductase (complex I)" and discusses its function in electron transport from NADH to ubiquinone. Reason: Valid NAS annotation consistent with other annotations for this activity. Supporting Evidence: PMID:9878551 NADH:ubiquinone oxidoreductase (complex I) is an extremely complicated multiprotein complex located in the inner mitochondrial membrane. Its main function is the transport of electrons from NADH to ubiquinone |
| GO:0009055 electron transfer activity | IBA GO_REF:0000033 | NEW | Summary: GO:0009055 (electron transfer activity) is not currently annotated for NDUFV1 in GOA but should be. NDUFV1 performs electron transfer as part of the NADH-to-ubiquinone chain: it accepts electrons from NADH at its FMN cofactor and transfers them to the [4Fe-4S] cluster N3, then onward to NDUFS1. This is analogous to the IBA annotation for SDHA with GO:0009055. The deep research review confirms this electron transfer role across the N-module Fe-S relay (file:human/NDUFV1/NDUFV1-deep-research-falcon.md). UniProt keywords include "Electron transport" (KW-0249). Reason: Electron transfer activity is a core molecular function of NDUFV1. The FMN cofactor accepts electrons from NADH and transfers them to the [4Fe-4S] cluster N3, continuing to the downstream Fe-S chain. This is the subunit-specific MF of NDUFV1 and is missing from the current annotation set. Analogous to SDHA's IBA annotation for GO:0009055. Proposed as an IBA rather than a direct annotation because the family review (interpro/panther/PTHR11780/PTHR11780-review.yaml) finds the machinery for it - the FMN site and all four N3 cysteine ligands - intact in every member checked from Escherichia coli to human, so the right place for the assertion is a node above the bacteria/eukaryote split. NDUFV1 currently receives no molecular-function IBA at all because the eukaryotic node PTN000207233 carries no F-aspect IBD; the family's only one, GO:0003954, sits on the bacterial node. Supporting Evidence: PMID:8288251 is believed to be the principal site of entry for electrons donated by NADH into the respiratory chain file:human/NDUFV1/NDUFV1-deep-research-falcon.md Electrons flow NADH to FMN (bound in NDUFV1) to series of Fe-S clusters to terminal cluster N2 near the ubiquinone site |
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