NDUFS1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0008137 NADH dehydrogenase (ubiquinone) activity	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation with 'contributes_to' qualifier for the complex-level NADH dehydrogenase (ubiquinone) activity. GO:0008137 represents the overall reaction of Complex I (NADH + ubiquinone + 5H+_in -> NAD+ + ubiquinol + 4H+_out). NDUFS1 is a core subunit of the N-module that harbors Fe-S clusters critical for electron relay, but the full catalytic cycle of Complex I requires all 45 subunits. The 'contributes_to' qualifier is appropriate and phylogenetically sound (PMID:31557978, PMID:30879903). Reason: NDUFS1 contributes to the NADH dehydrogenase ubiquinone activity of Complex I by providing key Fe-S clusters in the electron relay chain. The 'contributes_to' qualifier is correct because the full catalytic reaction requires multiple subunits. The IBA annotation is phylogenetically well-supported. This represents a core function of the gene product. Supporting Evidence: PMID:31557978 NDUFS1, encodes the NADH-ubiquinone oxidoreductase 75 kDa subunit, the largest subunit of CI that accommodates three iron-sulfur clusters in the N-module, which binds and oxidizes NADH PMID:30879903 MDM2 negatively regulates NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1), leading to decreased mitochondrial respiration file:human/NDUFS1/NDUFS1-deep-research-falcon.md NDUFS1 encodes the NADH:ubiquinone oxidoreductase 75 kDa core subunit of mitochondrial complex I in Homo sapiens. It is a core subunit of the hydrophilic N-module of complex I, positioned where NADH oxidation and iron-sulfur Fe-S chain electron transfer occur.
GO:0032981 mitochondrial respiratory chain complex I assembly	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for Complex I assembly. NDUFS1 plays a key role in the assembly and stability of Complex I as demonstrated by multiple studies. Mutations in NDUFS1 lead to decreased stability of the entire N-module and prevent proper Complex I assembly and supercomplex formation (PMID:31557978, PMID:30879903, PMID:16478720). This IBA is phylogenetically sound and well-supported experimentally. Reason: Core biological process for NDUFS1. Multiple experimental studies demonstrate that NDUFS1 mutations destabilize the N-module and impair Complex I assembly. The IBA annotation captures this conserved role accurately. Supporting Evidence: PMID:31557978 the biallelic mutations in NDUFS1 led to a decreased stability of the entire N-module of CI and disrupted the electron transfer between two iron-sulfur clusters PMID:16478720 The mutation (Q522K replacement) in NDUFS1 gene, coding for the 75-kDa Fe-S subunit of the complex, was associated with (a) reduced level of the mature complex
GO:1902600 proton transmembrane transport	IEA GO_REF:0000108	ACCEPT	Summary: IEA annotation inferred from GO:0008137 (NADH dehydrogenase ubiquinone activity) via logical inference. Complex I couples electron transfer to proton translocation, so proton transmembrane transport is a logical consequence of the NADH dehydrogenase activity. However, the proton-pumping machinery is located in the membrane arm (P-module) of Complex I, not in the peripheral arm N-module where NDUFS1 resides. NDUFS1 does not directly participate in proton translocation. As an IEA it is acceptable as a broader process annotation for a complex subunit, even though the proton pumping is mechanistically distant from NDUFS1's specific role. Reason: While proton translocation is mechanistically performed by the membrane arm subunits (not by NDUFS1), this is a legitimate broader process annotation for a Complex I subunit via logical inference from the complex-level activity. The annotation is acceptable as an IEA, albeit not the most informative for NDUFS1 specifically.
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for mitochondrial inner membrane localization. NDUFS1 is a peripheral membrane protein on the matrix side of the inner membrane, as part of Complex I. This is confirmed by cryo-EM structures (PMID:28844695) and UniProt subcellular location. Reason: Correct localization. NDUFS1 is part of Complex I which is embedded in the inner mitochondrial membrane. NDUFS1 specifically is on the matrix-facing peripheral arm but is associated with the membrane complex. 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
GO:0008137 NADH dehydrogenase (ubiquinone) activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for NADH dehydrogenase (ubiquinone) activity from combined automated methods. This uses the 'enables' qualifier (inferred from InterPro, EC number, etc.). The IBA annotation above uses the more appropriate 'contributes_to' qualifier. While the IEA is not wrong at the broad level, the 'enables' qualifier is less precise for a subunit of a multi-protein enzyme complex. Reason: Correct in terms of the function but the 'enables' qualifier from automated annotation is less precise than 'contributes_to' from the IBA. Acceptable as an IEA annotation since automated pipelines typically default to 'enables'.
GO:0016020 membrane	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for generic 'membrane' localization from InterPro. This is very broad. The more specific GO:0005743 (mitochondrial inner membrane) is also annotated. This IEA is not wrong but is uninformative given the availability of more specific terms. Reason: Correct but very generic. Acceptable for an IEA annotation as a broader parent of the more specific mitochondrial inner membrane annotation.
GO:0016491 oxidoreductase activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for general oxidoreductase activity from InterPro domain mappings. NDUFS1 is part of Complex I which catalyzes an oxidoreductase reaction (NADH oxidation coupled to ubiquinone reduction). This is a correct but very broad parent term. The more specific GO:0008137 (NADH dehydrogenase ubiquinone activity) is also annotated. Reason: Correct but general. Acceptable for IEA annotations to be broader than experimental annotations. The more specific GO:0008137 is also present.
GO:0016651 oxidoreductase activity, acting on NAD(P)H	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro for oxidoreductase activity acting on NAD(P)H. This is an intermediate-specificity term. Complex I oxidizes NADH (not NADPH), so GO:0016651 is accurate as a parent term of GO:0008137. Reason: Correct classification at an intermediate level. Complex I oxidizes NADH, which falls under the NAD(P)H-acting oxidoreductase class. Acceptable IEA annotation.
GO:0022904 respiratory electron transport chain	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for respiratory electron transport chain from UniProtKB keyword mapping. NDUFS1 is a core subunit of Complex I, the entry point of the mitochondrial respiratory electron transport chain. This is a correct and appropriate biological process annotation. Reason: Correct. NDUFS1 is part of Complex I which is the first enzyme of the respiratory electron transport chain. This is a core biological process annotation. Supporting Evidence: PMID:31557978 Complex I (CI, NADH:ubiquinone oxidoreductase) is the first and largest enzyme of the mitochondrial respiratory chain in humans
GO:0042773 ATP synthesis coupled electron transport	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro for ATP synthesis coupled electron transport. Complex I couples electron transfer from NADH to ubiquinone with proton translocation that drives ATP synthesis. This is a broader process annotation that accurately describes the physiological context of Complex I function. Reason: Correct. Complex I function is coupled to ATP synthesis via the proton motive force. This is an appropriate biological process annotation for a Complex I subunit.
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProtKB keyword mapping for metal ion binding. NDUFS1 binds iron ions as part of its [2Fe-2S] and [4Fe-4S] clusters. This is correct but very broad. More specific iron-sulfur cluster binding terms are also annotated. Reason: Correct but generic. NDUFS1 binds iron ions via its three Fe-S clusters. The more specific GO:0051536, GO:0051537, and GO:0051539 are also annotated and are more informative.
GO:0051536 iron-sulfur cluster binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for iron-sulfur cluster binding from combined automated methods. NDUFS1 binds one [2Fe-2S] cluster and two [4Fe-4S] clusters. This is a well-supported core molecular function of NDUFS1. UniProt documents the specific Fe-S cluster binding sites with PROSITE and sequence similarity evidence. Reason: Core molecular function. NDUFS1 contains three Fe-S clusters essential for electron relay in Complex I. Well supported by structural and biochemical evidence. Supporting Evidence: PMID:31557978 Val228 is located between the two iron-sulfur clusters N4 and N5 in subunit NDUFS1
GO:0051537 2 iron, 2 sulfur cluster binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for [2Fe-2S] cluster binding from UniProtKB keyword mapping. NDUFS1 binds one [2Fe-2S] cluster (designated N1b in EPR nomenclature) via its 2Fe-2S ferredoxin-type domain at residues 30-108. The binding residues are Cys64, Cys75, Cys78, and Cys92 according to UniProt. Reason: Correct. NDUFS1 binds one [2Fe-2S] cluster in its N-terminal ferredoxin domain. Supported by sequence analysis, domain architecture, and structural studies.
GO:0051539 4 iron, 4 sulfur cluster binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for [4Fe-4S] cluster binding from UniProtKB keyword mapping. NDUFS1 binds two [4Fe-4S] clusters (designated N4 and N5 in EPR nomenclature). The binding residues are documented in UniProt: cluster 1 via Cys124/Cys128/Cys131/His137 and cluster 2 via Cys176/Cys179/Cys182/Cys226. These clusters are critical for electron tunneling between the N- and Q-modules (PMID:31557978). Reason: Correct. NDUFS1 binds two [4Fe-4S] clusters that are essential for electron transfer. The Val228Ala mutation between clusters N4 and N5 reduces electron tunneling rate by 35-fold (PMID:31557978), demonstrating the functional importance of these clusters. Supporting Evidence: PMID:31557978 the residue Val228 was critical for bridging the electron transfer between the N4 and N5 clusters, as electrons tunnelled primarily through this relatively bulky residue
GO:0005515 protein binding	IPI PMID:24344204 TIMMDC1/C3orf1 functions as a membrane-embedded mitochondria...	KEEP AS NON CORE	Summary: IPI annotation for protein binding with NDUFA9 (Q16795) from Guarani et al. (2014). This study used interaction proteomics to map Complex I assembly factor associations. NDUFS1 interaction with NDUFA9 is expected as both are Complex I subunits. NDUFA9 is in the Q-module and NDUFS1 is at the N/Q-module interface. However, 'protein binding' is uninformative; the interaction reflects Complex I subunit assembly. Reason: The NDUFS1-NDUFA9 interaction reflects inter-subunit contacts within Complex I, which is already captured by the CC annotation for Complex I membership (GO:0045271). 'Protein binding' is uninformative as a GO term.
GO:0005515 protein binding	IPI PMID:29128334 A Map of Human Mitochondrial Protein Interactions Linked to ...	KEEP AS NON CORE	Summary: IPI annotation for protein binding with SOAT1 (P35610) from Malty et al. (2017). This was a large-scale mitochondrial protein interaction map. The biological significance of an NDUFS1-SOAT1 interaction is unclear. SOAT1 is an ER-localized acyl-CoA:cholesterol acyltransferase, and an interaction with a mitochondrial matrix protein is unlikely to be functionally meaningful. Reason: High-throughput protein-protein interaction data. The NDUFS1-SOAT1 interaction has no known biological relevance and may be an artifact. 'Protein binding' is uninformative.
GO:0005515 protein binding	IPI PMID:32807793 OSMR controls glioma stem cell respiration and confers resis...	KEEP AS NON CORE	Summary: IPI annotation for protein binding with OSMR (Q99650) from Sharanek et al. (2020). This study demonstrated that OSMR is targeted to the mitochondrial matrix and interacts with NDUFS1/NDUFS2 of Complex I to promote mitochondrial respiration. The interaction was validated by co-immunoprecipitation. This is a biologically meaningful regulatory interaction, though 'protein binding' is uninformative. Reason: The OSMR-NDUFS1 interaction is biologically interesting (OSMR promotes Complex I respiration in glioma stem cells), but this is a regulatory/pathological context interaction, not a core function of NDUFS1. 'Protein binding' is uninformative. Supporting Evidence: PMID:32807793 OSMR interacts with NADH ubiquinone oxidoreductase 1/2 (NDUFS1/2) of complex I and promotes mitochondrial respiration
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: IPI annotation for protein binding with NDUFA9 (Q16795) from Huttlin et al. (2021) dual proteome-scale network study. Confirms the NDUFS1-NDUFA9 Complex I subunit interaction. Already captured by Complex I membership annotation. Reason: Redundant confirmation of a known Complex I subunit interaction. 'Protein binding' is uninformative; the interaction is already captured by GO:0045271 (part_of respiratory chain complex I).
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	KEEP AS NON CORE	Summary: IPI annotation for protein binding with NDUFA9 (Q16795) from Schaffer et al. (2025) multimodal cell maps study. Third detection of NDUFS1-NDUFA9 interaction. These are fellow Complex I subunits. Reason: Yet another confirmation of the NDUFS1-NDUFA9 Complex I subunit interaction. 'Protein binding' is uninformative.
GO:0005739 mitochondrion	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for mitochondrial localization via Ensembl Compara ortholog transfer. NDUFS1 has a mitochondrial transit peptide (residues 1-23, cleaved after Thr-23) and is well-established as a mitochondrial protein. Multiple IDA annotations also confirm this localization. Reason: Correct localization, well-supported by transit peptide, IDA evidence, and proteomics data.
GO:0009055 electron transfer activity	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for electron transfer activity via Ensembl Compara ortholog transfer from mouse (Q91VD9). NDUFS1 contains three Fe-S clusters that form part of the electron relay chain in Complex I, transferring electrons from FMN toward ubiquinone. This is the subunit-specific molecular function of NDUFS1 -- it enables electron transfer activity independently via its Fe-S clusters (file:human/NDUFS1/NDUFS1-deep-research-falcon.md). Reason: This is the core subunit-specific molecular function of NDUFS1. The three Fe-S clusters in NDUFS1 directly participate in electron transfer within Complex I. Unlike the complex-level NADH dehydrogenase activity (which NDUFS1 'contributes_to'), electron transfer activity is an intrinsic property of the NDUFS1 subunit. Supporting Evidence: PMID:1935949 Determination of the cDNA sequence for the human mitochondrial 75-kDa Fe-S protein of NADH-coenzyme Q reductase PMID:31557978 the residue Val228 was critical for bridging the electron transfer between the N4 and N5 clusters
GO:0032981 mitochondrial respiratory chain complex I assembly	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for Complex I assembly from combined automated methods. Redundant with the IBA and IMP annotations for the same term. Consistent with experimental data. Reason: Correct and consistent with IBA and IMP annotations for the same term. Duplicates are expected when multiple evidence sources converge.
GO:0045271 respiratory chain complex I	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for Complex I membership from combined automated methods. NDUFS1 is a core subunit of Complex I, confirmed by immunopurification and mass spectrometry (PMID:12611891) and cryo-EM structures (PMID:28844695). Reason: Correct. NDUFS1 is a core subunit of respiratory chain Complex I. Well established by multiple experimental approaches.
GO:0005739 mitochondrion	IDA GO_REF:0000052	ACCEPT	Summary: IDA annotation for mitochondrial localization from HPA immunofluorescence curation. Direct experimental evidence supporting NDUFS1 mitochondrial localization. Reason: Direct experimental evidence from immunofluorescence. Consistent with all other localization data.
GO:0005743 mitochondrial inner membrane	IDA PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ...	ACCEPT	Summary: IDA annotation from ComplexPortal based on cryo-EM structure of the human respiratory megacomplex I2III2IV2 (Guo et al. 2017). This study resolved the architecture of Complex I in the inner membrane context, directly demonstrating NDUFS1 as part of the membrane-associated complex. Reason: Direct structural evidence from cryo-EM. The megacomplex structure shows Complex I (including NDUFS1) embedded in the inner mitochondrial membrane. 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-...	ACCEPT	Summary: NAS annotation from ComplexPortal based on the review by Signes and Fernandez-Vizarra (2018) on OXPHOS complex assembly. Complex I is the entry point for NADH-derived electrons into the respiratory chain, a core component of aerobic respiration. This is a broad but correct biological process annotation. Reason: Correct. Complex I is essential for aerobic respiration. NDUFS1, as a core subunit, participates in this process. Acceptable as a broader process annotation. Supporting Evidence: PMID:30030361 The assembly of the five oxidative phosphorylation system (OXPHOS) complexes in the inner mitochondrial membrane is an intricate 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 for proton motive force-driven mitochondrial ATP synthesis. Complex I couples electron transfer to proton pumping, generating part of the proton motive force that drives ATP synthase. However, NDUFS1 is in the N-module peripheral arm and does not directly participate in proton translocation (which occurs in the membrane arm P-module). Nevertheless, Complex I as a whole does contribute to the proton motive force, and NDUFS1's electron transfer activity is mechanistically coupled to this proton pumping. This is acceptable as a broader process annotation for a Complex I subunit, though it is less directly applicable to NDUFS1 than to membrane arm subunits. Reason: Complex I does contribute to the proton motive force driving ATP synthesis, but NDUFS1 is in the N-module and does not directly participate in proton translocation. The annotation is not wrong at the complex level but is peripherally related to NDUFS1's specific role. Keep as non-core rather than removing (unlike for Complex II subunits which truly do not pump protons, Complex I does pump protons as part of its catalytic cycle).
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: HTP annotation for mitochondrial localization from quantitative high-confidence human mitochondrial proteome study (Morgenstern et al. 2021). NDUFS1 was identified in the mitochondrial proteome. Reason: Correct. NDUFS1 is a well-established mitochondrial protein confirmed by proteomics.
GO:0032981 mitochondrial respiratory chain complex I assembly	IMP PMID:16478720 Dysfunctions of cellular oxidative metabolism in patients wi...	ACCEPT	Summary: IMP annotation from Iuso et al. (2006). This study investigated the pathogenic mechanism of a C1564A mutation in the NDUFS1 gene (Q522K replacement) and found it was associated with reduced level of the mature complex, demonstrating NDUFS1's role in Complex I assembly. Reason: Direct experimental evidence showing NDUFS1 mutations impair Complex I assembly. The Q522K mutation caused reduced levels of mature Complex I in patient fibroblasts. Supporting Evidence: PMID:16478720 The mutation (Q522K replacement) in NDUFS1 gene, coding for the 75-kDa Fe-S subunit of the complex, was associated with (a) reduced level of the mature complex
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). This study used immunocapture followed by mass spectrometry to identify all subunits of human Complex I, directly demonstrating NDUFS1 as a component of the purified complex. Reason: Direct experimental identification of NDUFS1 as a subunit of immunopurified human Complex I by mass spectrometry. Core structural annotation. 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:16478720 Dysfunctions of cellular oxidative metabolism in patients wi...	ACCEPT	Summary: IMP annotation from Iuso et al. (2006). NDUFS1 mutation (Q522K) leads to reduced level of the mature Complex I, demonstrating NDUFS1's role as a subunit of the complex. Reason: IMP evidence from mutant analysis demonstrating NDUFS1 is required for mature Complex I. Consistent with IDA evidence. Supporting Evidence: PMID:16478720 The mutation (Q522K replacement) in NDUFS1 gene, coding for the 75-kDa Fe-S subunit of the complex, was associated with (a) reduced level of the mature complex
GO:0045271 respiratory chain complex I	NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox...	ACCEPT	Summary: NAS annotation from Loeffen et al. (1998). This study completed the characterization of all human Complex I cDNAs, discussing NDUFS1 as a known subunit of the complex. Reason: Correct. NDUFS1 is well-established as a Complex I subunit. This early characterization study placed it in the complex context. 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:30879903 MDM2 Integrates Cellular Respiration and Apoptotic Signaling...	ACCEPT	Summary: IMP annotation with 'enables' qualifier from Elkholi et al. (2019). This study showed that MDM2 binds NDUFS1, preventing its mitochondrial localization and causing Complex I destabilization and loss of oxidative phosphorylation efficiency. The IMP evidence demonstrates that NDUFS1 is required for NADH dehydrogenase activity. Note the GOA TSV uses 'enables' qualifier here, while the IBA and older IMP annotations use 'contributes_to'. For GO:0008137 representing the full complex reaction, 'contributes_to' is more precise, but 'enables' is defensible for the core catalytic subunit. Reason: Valid IMP evidence. MDM2 sequestration of NDUFS1 leads to decreased Complex I activity, demonstrating NDUFS1 is essential for the NADH dehydrogenase activity. The 'enables' vs 'contributes_to' qualifier difference from the IBA is acceptable. Supporting Evidence: PMID:30879903 MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial localization and ultimately causing complex I and supercomplex destabilization and inefficiency of oxidative phosphorylation
GO:0008137 NADH dehydrogenase (ubiquinone) activity	IMP PMID:31557978 Mutations in NDUFS1 Cause Metabolic Reprogramming and Disrup...	ACCEPT	Summary: IMP annotation with 'enables' qualifier from Ni et al. (2019). This study characterized NDUFS1 mutations (V228A and D252G) and showed they caused loss of Complex I catalytic activity and disrupted electron transfer between iron-sulfur clusters N4 and N5. In-gel activity assays revealed almost no enzymatic activity in the NDUFS1 mutant. Reason: Strong IMP evidence. NDUFS1 mutations directly abolish Complex I enzymatic activity, with almost no in-gel activity and dramatic reduction in electron tunneling rate (35-fold decrease for V228A). Demonstrates NDUFS1 is essential for the NADH dehydrogenase activity. Supporting Evidence: PMID:31557978 the biallelic mutations in NDUFS1 led to a decreased stability of the entire N-module of CI and disrupted the electron transfer between two iron-sulfur clusters
GO:0006120 mitochondrial electron transport, NADH to ubiquinone	IMP PMID:31557978 Mutations in NDUFS1 Cause Metabolic Reprogramming and Disrup...	ACCEPT	Summary: IMP annotation from Ni et al. (2019). NDUFS1 mutations disrupt electron transfer within Complex I, specifically between iron-sulfur clusters N4 and N5. Seahorse respiration assays showed basal respiration, ATP-linked respiration, maximal respiration, and spare respiratory capacity were all less than 50% of controls. Reason: Core biological process annotation. Direct experimental evidence that NDUFS1 mutations impair mitochondrial electron transport from NADH to ubiquinone. The electron tunneling calculations provide mechanistic insight into how NDUFS1 mediates this process. Supporting Evidence: PMID:31557978 the basal respiration, ATP-linked respiration, maximal respiration, and the spare respiration capacity were less than 50% compared with controls
GO:0005515 protein binding	IPI PMID:30879903 MDM2 Integrates Cellular Respiration and Apoptotic Signaling...	KEEP AS NON CORE	Summary: IPI annotation for NDUFS1 interaction with MDM2 (Q00987) from Elkholi et al. (2019). MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial localization. This is a biologically significant regulatory interaction -- MDM2's amino-terminal region is sufficient to bind NDUFS1, alter supercomplex assembly, and induce apoptosis. The interaction is independent of p53. However, 'protein binding' is uninformative. Reason: The MDM2-NDUFS1 interaction is biologically significant (MDM2 regulates Complex I through NDUFS1), but it represents a regulatory interaction, not a core molecular function of NDUFS1. 'Protein binding' is uninformative as a GO term. Supporting Evidence: PMID:30879903 MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial localization and ultimately causing complex I and supercomplex destabilization
GO:0005739 mitochondrion	IDA PMID:30879903 MDM2 Integrates Cellular Respiration and Apoptotic Signaling...	ACCEPT	Summary: IDA annotation for mitochondrial localization from Elkholi et al. (2019). This study used subcellular fractionation and immunoblotting to demonstrate NDUFS1 mitochondrial localization, as well as showing that MDM2 prevents NDUFS1 from reaching mitochondria. Reason: Direct experimental evidence for mitochondrial localization, consistent with all other data. Supporting Evidence: PMID:30879903 MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial localization
GO:0032981 mitochondrial respiratory chain complex I assembly	IMP PMID:30879903 MDM2 Integrates Cellular Respiration and Apoptotic Signaling...	ACCEPT	Summary: IMP annotation from Elkholi et al. (2019). MDM2-mediated sequestration of NDUFS1 caused complex I and supercomplex destabilization, demonstrating NDUFS1's role in assembly and stability of Complex I. Reason: IMP evidence showing that preventing NDUFS1 mitochondrial localization (via MDM2 sequestration) destabilizes Complex I assembly and supercomplexes. Supporting Evidence: PMID:30879903 MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial localization and ultimately causing complex I and supercomplex destabilization
GO:0032981 mitochondrial respiratory chain complex I assembly	IMP PMID:31557978 Mutations in NDUFS1 Cause Metabolic Reprogramming and Disrup...	ACCEPT	Summary: IMP annotation from Ni et al. (2019). NDUFS1 mutations led to decreased stability of the entire N-module and impaired supercomplex formation. BN-PAGE showed only a small fraction of supercomplexes were formed compared to controls. Reason: Strong IMP evidence. Mutations in NDUFS1 specifically destabilize the N-module of Complex I and prevent proper supercomplex formation. Supporting Evidence: PMID:31557978 Only a small fraction of supercomplexes were formed compared to controls
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-163217	ACCEPT	Summary: TAS annotation from Reactome for mitochondrial matrix localization, based on the Complex I NADH oxidation reaction. NDUFS1 is a peripheral membrane protein on the matrix side of Complex I. UniProt states NDUFS1 is on the matrix side of the inner membrane. Reason: Correct. NDUFS1 is in the peripheral arm of Complex I facing the mitochondrial matrix. This is the most specific correct localization for NDUFS1.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-6788523	ACCEPT	Summary: TAS annotation from Reactome for mitochondrial matrix localization, associated with NUBPL-mediated 4Fe-4S cluster transfer to Complex I subunits. NDUFS1 receives its Fe-S clusters in the mitochondrial matrix. Reason: Correct. Fe-S cluster insertion into NDUFS1 occurs in the mitochondrial matrix.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-6799179	ACCEPT	Summary: TAS from Reactome for matrix localization, associated with peripheral arm subunits binding to the 815 kDa complex to form a 980 kDa complex during Complex I assembly. Reason: Correct. Assembly intermediates involving NDUFS1 form in the mitochondrial matrix.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-6799196	ACCEPT	Summary: TAS from Reactome for matrix localization, associated with the MCIA complex and NDUFAF2-7 dissociation from the 980 kDa complex to yield mature Complex I. Reason: Correct. Final assembly steps involving NDUFS1 occur in the mitochondrial matrix.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-6800870	ACCEPT	Summary: TAS from Reactome for matrix localization, associated with NDUF subunits binding to form the FP subcomplex. Reason: Correct. The FP (flavoprotein) subcomplex of the N-module forms in the mitochondrial matrix.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838035	ACCEPT	Summary: TAS from Reactome for matrix localization, associated with CLPXP binding mitochondrial matrix proteins. This reflects the general mitochondrial matrix localization of NDUFS1 in the context of mitochondrial quality control/protein degradation. Reason: Correct. NDUFS1 is a matrix protein subject to mitochondrial quality control.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838081	ACCEPT	Summary: TAS from Reactome for matrix localization, associated with LONP1 degradation of mitochondrial matrix proteins. Reflects NDUFS1 as a LONP1 substrate in the matrix. Reason: Correct. NDUFS1 is a mitochondrial matrix protein and potential substrate for LONP1 protease.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838093	ACCEPT	Summary: TAS from Reactome for matrix localization, associated with LONP1 binding mitochondrial matrix proteins. Reason: Correct and consistent with other matrix localization annotations.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838289	ACCEPT	Summary: TAS from Reactome for matrix localization, associated with CLPXP degradation of mitochondrial matrix proteins. Reason: Correct and consistent with other matrix localization annotations.
GO:0008137 NADH dehydrogenase (ubiquinone) activity	IMP PMID:15824269 Leigh syndrome associated with mitochondrial complex I defic...	ACCEPT	Summary: IMP annotation with 'contributes_to' qualifier from Martin et al. (2005). This study identified a novel homozygous L231V mutation in NDUFS1 in a patient with Leigh syndrome and Complex I deficiency. Muscle biochemistry showed a Complex I defect. The 'contributes_to' qualifier is appropriate for a subunit contribution to the complex-level activity. Reason: Valid IMP evidence. NDUFS1 mutation causes Complex I deficiency, demonstrating that NDUFS1 contributes to the NADH dehydrogenase activity. The 'contributes_to' qualifier is the correct usage for a subunit of a multi-protein enzyme complex. Supporting Evidence: PMID:15824269 RESULTS: Muscle biochemistry results showed a complex I defect of the mitochondrial respiratory chain.
GO:0008137 NADH dehydrogenase (ubiquinone) activity	IMP PMID:16870178 cAMP controls oxygen metabolism in mammalian cells.	ACCEPT	Summary: IMP annotation with 'contributes_to' qualifier from Piccoli et al. (2006). This study showed that a genetic defect in the 75 kDa Fe-S protein subunit (NDUFS1) of Complex I resulted in inhibition of complex activity and enhanced ROS production, which were reversed by cAMP. Reason: Valid IMP evidence. NDUFS1 defect causes Complex I activity inhibition and ROS production. The 'contributes_to' qualifier is appropriate. Supporting Evidence: PMID:16870178 In fibroblasts from a patient a genetic defect in the 75 kDa FeS-protein subunit of complex I resulted in inhibition of the activity of the complex and enhanced ROS production, which were reversed by cAMP
GO:0008137 NADH dehydrogenase (ubiquinone) activity	IMP PMID:16478720 Dysfunctions of cellular oxidative metabolism in patients wi...	ACCEPT	Summary: IMP annotation with 'contributes_to' qualifier from Iuso et al. (2006). The Q522K mutation in NDUFS1 caused marked but not complete inhibition of Complex I activity. Reason: Valid IMP evidence showing that NDUFS1 mutation impairs Complex I activity. The 'contributes_to' qualifier is appropriate. Supporting Evidence: PMID:16478720 The mutation (Q522K replacement) in NDUFS1 gene, coding for the 75-kDa Fe-S subunit of the complex, was associated with (a) reduced level of the mature complex, (b) marked, albeit not complete, inhibition of the activity
GO:0005515 protein binding	IPI PMID:15186778 Disruption of mitochondrial function during apoptosis is med...	KEEP AS NON CORE	Summary: IPI annotation for NDUFS1 interaction with NDUFS3 (O75251) from Ricci et al. (2004). This study identified NDUFS1 as a critical caspase substrate in the mitochondria during apoptosis. The interaction with NDUFS3 reflects that both are Complex I subunits (NDUFS3 is in the Q-module adjacent to the N-module). 'Protein binding' is uninformative. Reason: The NDUFS1-NDUFS3 interaction reflects inter-subunit contacts within Complex I. 'Protein binding' is uninformative. The interaction is already captured by GO:0045271.
GO:0005758 mitochondrial intermembrane space	IDA PMID:15186778 Disruption of mitochondrial function during apoptosis is med...	KEEP AS NON CORE	Summary: IDA annotation for mitochondrial intermembrane space localization from Ricci et al. (2004). This study showed that cleaved NDUFS1 fragments are released into the intermembrane space during apoptosis after caspase cleavage. The uncleaved, functional NDUFS1 is located on the matrix side of the inner membrane. This annotation likely refers to the detection of NDUFS1 (or its fragments) in the IMS context during apoptosis, which is not the normal steady-state localization. The normal localization is the matrix face of Complex I. Reason: NDUFS1 detection in the intermembrane space likely reflects the apoptotic context (caspase cleavage releasing fragments). The steady-state localization of functional NDUFS1 is the mitochondrial matrix face. This annotation is not wrong but reflects a non-standard, apoptosis-specific context. Supporting Evidence: PMID:15186778 we identify NDUFS1, the 75 kDa subunit of respiratory complex I, as a critical caspase substrate in the mitochondria
GO:0045333 cellular respiration	IMP PMID:15186778 Disruption of mitochondrial function during apoptosis is med...	ACCEPT	Summary: IMP annotation from Ricci et al. (2004). This study showed that cells expressing a noncleavable mutant of p75/NDUFS1 sustain mitochondrial membrane potential and ATP levels during apoptosis, demonstrating NDUFS1's role in maintaining cellular respiration. This is a correct broader process annotation for NDUFS1. Reason: Valid IMP evidence. Noncleavable NDUFS1 sustains respiration during apoptosis, directly demonstrating NDUFS1's role in cellular respiration. Supporting Evidence: PMID:15186778 Cells expressing a noncleavable mutant of p75 sustain DeltaPsim and ATP levels during apoptosis, and ROS production in response to apoptotic stimuli is dampened
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). This study completed the characterization of human Complex I cDNAs and discussed the complex's function in electron transport from NADH to ubiquinone. Reason: Correct core biological process. Consistent with the IMP annotation from PMID:31557978 for the same term. 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) for NADH dehydrogenase activity. This study discusses Complex I's overall enzymatic function. Reason: Correct. Consistent with multiple IMP and IBA annotations for this term. Supporting Evidence: PMID:9878551 NADH:ubiquinone oxidoreductase (complex I) is an extremely complicated multiprotein complex located in the inner mitochondrial membrane
GO:0009055 electron transfer activity	NAS PMID:1935949 Determination of the cDNA sequence for the human mitochondri...	ACCEPT	Summary: NAS annotation from Chow et al. (1991), the original study determining the cDNA sequence for the human 75 kDa Fe-S protein. The title itself identifies NDUFS1 as a "Fe-S protein of NADH-coenzyme Q reductase," establishing its electron transfer function via Fe-S clusters. This is the core subunit-specific molecular function. Reason: Core molecular function annotation. The original characterization of NDUFS1 identified it as an iron-sulfur protein, establishing its role in electron transfer. This is the most appropriate subunit-specific MF for NDUFS1. Supporting Evidence: PMID:1935949 Determination of the cDNA sequence for the human mitochondrial 75-kDa Fe-S protein of NADH-coenzyme Q reductase

Gene Description

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