NDUFS2 encodes the 49 kDa subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase, EC 7.1.1.2), and is a core catalytic subunit of the Q-module in the peripheral (matrix-facing) arm. NDUFS2 directly contributes to the ubiquinone-binding channel, providing the conserved His59/Tyr108 residue pair that contacts and orients the ubiquinone headgroup during reduction. A [4Fe-4S] cluster has been assigned to NDUFS2 by similarity to the NiFe-hydrogenase large subunit fold it retains, but no structure of mammalian Complex I places a cluster on this subunit; the terminal N2 cluster that delivers electrons to the quinone site is ligated by NDUFS7. NDUFS2 is essential for both Complex I assembly and catalytic activity. NDUFS2 is dimethylated at Arg-85 (Arg-118 in precursor numbering) by the assembly factor NDUFAF7, a modification required for stabilization of early assembly intermediates. NDUFS2 is also a redox-sensitive component implicated in acute oxygen sensing in pulmonary artery smooth muscle cells, where its cysteine residues become reduced under hypoxia, inhibiting Complex I and triggering hypoxic pulmonary vasoconstriction. Pathogenic mutations cause mitochondrial Complex I deficiency (MC1DN6, presenting as Leigh syndrome) and Leber-like hereditary optic neuropathy (LHONAR2).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005743 mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for mitochondrial inner membrane localization. NDUFS2 is a core subunit of Complex I which is anchored in the inner mitochondrial membrane. NDUFS2 resides in the peripheral arm at the junction with the membrane arm, on the matrix side, as confirmed by cryo-EM structures (PMID:28844695). The phylogenetic inference is sound and consistent with all experimental evidence. Reason: NDUFS2 is an integral component of Complex I which is embedded in the mitochondrial inner membrane. The IBA annotation is phylogenetically well-supported and experimentally confirmed by cryo-EM structural studies and immunodetection. 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:9585441 Mapping to 1q23 of the human gene (NDUFS2) encoding the 49-kDa subunit of the mitochondrial respiratory Complex I and immunodetection of the mature protein in mitochondria |
| 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 (EC 7.1.1.2). NDUFS2 is a core catalytic subunit that forms the ubiquinone-binding channel with its conserved His59/Tyr108 residue pair, directly participating in ubiquinone reduction. The 'contributes_to' qualifier is correct because the full reaction (NADH + ubiquinone + 5H+_in -> NAD+ + ubiquinol + 4H+_out) requires the entire 45-subunit complex. Multiple studies demonstrate that NDUFS2 mutations impair Complex I catalytic activity (PMID:22036843, PMID:28031252, PMID:30922174). Reason: Core function of NDUFS2. The 'contributes_to' qualifier is appropriate because NDUFS2 is a subunit of the multi-subunit Complex I holoenzyme. NDUFS2 is particularly critical because it contains the ubiquinone-binding site, making it essential for catalysis. The IBA is phylogenetically sound and strongly supported experimentally. Supporting Evidence: PMID:22036843 Complex I amounts in the patient carrying the Asp446Asn mutation were normal, while the complex I activity was strongly reduced, showing that the NDUFS2 mutation affects complex I enzymatic function PMID:30922174 In PASMC, siNdufs2 (cells/tissue treated with Ndufs2 siRNA) decreased normoxic H2O2, prevented hypoxic increases in [Ca2+]i, and mimicked aspects of chronic hypoxia, including decreasing Complex I activity, elevating the nicotinamide adenine dinucleotide (NADH/NAD+) ratio file:human/NDUFS2/NDUFS2-deep-research-falcon.md NDUFS2 is a catalytic/structural subunit of complex I embedded in the matrix-arm Q-module, shaping the Q-channel where NADH-derived electrons (via FMN and Fe-S clusters to N2) reduce ubiquinone |
| GO:0045271 respiratory chain complex I | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for localization to respiratory chain complex I. NDUFS2 is a core subunit of Complex I, identified as a component of the immunopurified human NADH dehydrogenase (PMID:12611891). This is a fundamental and unambiguous annotation for NDUFS2. Reason: Core CC annotation. NDUFS2 is an integral, well-established subunit of respiratory chain Complex I. The IBA is phylogenetically well-supported and confirmed by multiple experimental studies including mass spectrometry identification and cryo-EM structures. 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:0006120 mitochondrial electron transport, NADH to ubiquinone | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for the biological process of mitochondrial electron transport from NADH to ubiquinone. As a core catalytic subunit of Complex I that directly contributes to the ubiquinone-binding site and reduction, NDUFS2 is centrally involved in this process. Knockdown of NDUFS2 impairs Complex I-dependent electron transport (PMID:30922174). Reason: Core biological process for NDUFS2. The protein is essential for the catalytic cycle of Complex I, directly participating in ubiquinone reduction. The IBA is well-supported phylogenetically and experimentally. Supporting Evidence: PMID:30922174 In PASMC, siNdufs2 (cells/tissue treated with Ndufs2 siRNA) decreased normoxic H2O2, prevented hypoxic increases in [Ca2+]i, and mimicked aspects of chronic hypoxia, including decreasing Complex I activity, elevating the nicotinamide adenine dinucleotide (NADH/NAD+) ratio PMID:22036843 the complex I activity was strongly reduced, showing that the NDUFS2 mutation affects complex I enzymatic function |
| 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 across the inner membrane. NDUFS2 does not directly participate in proton pumping, which is performed by the membrane arm subunits (ND2, ND4, ND5). However, the Q-site region where NDUFS2 resides is mechanistically coupled to the proton-pumping machinery via hydrated channels and the E-channel (Grba et al. 2023, Sci Adv). As an IEA for a Complex I subunit, this is acceptable as a broader process annotation. Reason: While proton translocation is performed by the membrane arm, this is a legitimate broader process annotation for a Complex I subunit. The coupling between NDUFS2's Q-site and proton pumping is mechanistically real, though the annotation is not the most informative for NDUFS2 specifically. |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for mitochondrial inner membrane localization, consistent with the IBA annotation and cryo-EM structural data (PMID:28844695). NDUFS2 is a peripheral membrane protein on the matrix side of the inner membrane. Reason: Correct localization, consistent with the IBA and experimental evidence. Redundant with the IBA but acceptable as an independent IEA line. |
| GO:0008137 NADH dehydrogenase (ubiquinone) activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for NADH dehydrogenase (ubiquinone) activity. Consistent with the IBA and multiple experimental annotations for this core function. Reason: Correct MF annotation, consistent with IBA and experimental evidence. Redundant but acceptable as an independent IEA. |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation from UniProt keyword mapping. Oxidoreductase activity is a very broad parent term. NDUFS2 contributes to the oxidoreductase activity of Complex I (EC 7.1.1.2), specifically via the ubiquinone reduction step. This is a valid but non-informative parent of the more specific GO:0008137. Reason: While very general, this is not wrong for an IEA. The more specific GO:0008137 term is annotated separately. This broad IEA is acceptable as a parent-level annotation. |
| GO:0016651 oxidoreductase activity, acting on NAD(P)H | IEA GO_REF:0000002 | ACCEPT | Summary: IEA from InterPro mapping. GO:0016651 is a direct parent of GO:0008137 (NADH dehydrogenase (ubiquinone) activity), which is separately annotated to NDUFS2 by IBA, IEA, IMP and NAS lines and accepted in this review. Read at the level of the holoenzyme reaction that NDUFS2 contributes to, this parent term is therefore correct, if uninformative. The caveat worth recording is that NDUFS2 does not itself contact NAD(P)H: the nucleotide-binding site and FMN sit on NDUFV1 in the N-module, while NDUFS2 forms the quinone-binding channel at the far end of the Fe-S wire. Reason: Retained as a redundant broad parent of the accepted GO:0008137 annotations, consistent with the treatment of the equally broad GO:0016491 IEA. Replacing it with quinone binding would not be a refinement but a substitution of a different molecular function, so MODIFY is not the right instrument here; the quinone-site function of NDUFS2 is instead captured directly by the GO:0048039 (ubiquinone binding) annotation proposed below. |
| GO:0022904 respiratory electron transport chain | IEA GO_REF:0000043 | ACCEPT | Summary: IEA from UniProt keyword mapping for the respiratory electron transport chain process. NDUFS2 is a core subunit of Complex I, the first complex of the respiratory chain. This is a valid broader process annotation. Reason: Correct broader process annotation. Complex I is the entry point for NADH-derived electrons into the respiratory chain, and NDUFS2 is a core catalytic subunit. The more specific GO:0006120 is annotated separately. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA from UniProt keyword mapping for metal ion binding. NDUFS2 binds one [4Fe-4S] cluster via three conserved cysteine residues (Cys326, Cys332, Cys347 in precursor numbering per UniProt). This is a valid but very broad annotation; the more specific GO:0051539 (4 iron, 4 sulfur cluster binding) is also annotated. Reason: Correct but very general. NDUFS2 does bind iron via its [4Fe-4S] cluster. The more specific term GO:0051539 is also annotated. This broad IEA is acceptable. |
| GO:0048038 quinone binding | IEA GO_REF:0000002 | MODIFY | Summary: IEA from InterPro mapping for quinone binding. NDUFS2 contains the ubiquinone-binding channel with the conserved His59/Tyr108 residue pair that directly contacts the quinone headgroup. This is a core molecular function of NDUFS2. A more specific child term GO:0048039 (ubiquinone binding) exists and would be more precise. Reason: NDUFS2 specifically binds ubiquinone (coenzyme Q), not quinones generically. The more specific term GO:0048039 (ubiquinone binding) would be more appropriate given the well-characterized structural evidence of NDUFS2 forming the ubiquinone-binding channel with His59/Tyr108 contacting the ubiquinone headgroup. Proposed replacements: ubiquinone binding Supporting Evidence: file:human/NDUFS2/NDUFS2-deep-research-falcon.md NDUFS2-His59 (His59) is a quinone/ligand-contacting residue implicated in H-bonding and stabilization of the quinone head; Tyr108 locates near the redox site and contributes to headgroup interactions |
| GO:0051287 NAD binding | IEA GO_REF:0000002 | REMOVE | Summary: IEA from InterPro mapping for NAD binding. While Complex I as a whole binds and oxidizes NADH, the NADH-binding site is on NDUFV1 (51 kDa subunit) in the N-module, not on NDUFS2 in the Q-module. NDUFS2 does not directly bind NAD/NADH. This annotation appears to be an over-annotation arising from InterPro domain annotation of the broader Complex I family. Reason: NDUFS2 does not bind NAD or NADH. The NADH-binding site in Complex I is located on the NDUFV1 (51 kDa) subunit in the N-module, which also contains the FMN cofactor. NDUFS2 is in the Q-module and binds ubiquinone, not NADH. This IEA is likely a spurious transfer from the broader Complex I domain family annotation. |
| GO:0051536 iron-sulfur cluster binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA from UniProt keyword mapping for iron-sulfur cluster binding. UniProt annotates one [4Fe-4S] cluster on NDUFS2, but by similarity (ECO:0000255) rather than experimentally. This is a valid parent term; the more specific GO:0051539 is also annotated. Reason: Retained by deference to the UniProt cofactor annotation that generates this IEA, with the same by-similarity caveat noted on GO:0051539. Valid broader term complementing the more specific GO:0051539 annotation. |
| GO:0051539 4 iron, 4 sulfur cluster binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA from UniProt keyword mapping. UniProt annotates one [4Fe-4S] cluster with three conserved cysteine ligands (Cys326, Cys332, Cys347 in precursor numbering), but on ECO:0000255 (by-similarity) evidence only, inferred from the NiFe-hydrogenase large subunit fold that NDUFS2 retains. This cluster is NOT N2: in mammalian Complex I the eight Fe-S clusters are accounted for by NDUFV1 (N3), NDUFV2 (N1a), NDUFS1 (N1b/N4/N5), NDUFS7/PSST (N2) and NDUFS8 (N6a/N6b). The historical attribution of N2 to the 49 kDa subunit is a pre-structural EPR-era assignment superseded by cryo-EM. Reason: Retained by deference to the UniProt cofactor annotation, which is the source of this IEA. Note the evidence is by-similarity (ECO:0000255), not experimental, and no structure assigns an Fe-S cluster to NDUFS2; the catalytically important contribution of NDUFS2 is the ubiquinone-binding channel, not Fe-S-mediated electron transfer. MARK_AS_OVER_ANNOTATED would also be defensible here. |
| GO:0005515 protein binding | IPI PMID:15250827 Structural organization of mitochondrial human complex I: ro... | MARK AS OVER ANNOTATED | Summary: IPI annotation for protein binding from a study on structural organization of human Complex I, examining interaction with prohibitin and role of ND4/ND5 subunits (PMID:15250827). NDUFS2 interacts with multiple other Complex I subunits as part of the holoenzyme, but 'protein binding' is uninformative. Reason: Generic 'protein binding' does not convey useful information about NDUFS2 function. The interaction is likely within the context of the Complex I holoenzyme. Subunit-subunit interactions within a multi-protein complex are expected and captured by the CC annotation to GO:0045271 (respiratory chain complex I). |
| 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: IPI annotation from a mass spectrometry study analyzing protein complexes via blue native gel electrophoresis (PMID:19688755). The study identified NDUFS2 as part of Complex I. This is a high-throughput detection of known complex membership. Reason: Generic 'protein binding' from a high-throughput study confirming known Complex I membership. Uninformative as a MF annotation. |
| GO:0005515 protein binding | IPI PMID:24344204 TIMMDC1/C3orf1 functions as a membrane-embedded mitochondria... | MARK AS OVER ANNOTATED | Summary: IPI from a study identifying TIMMDC1 as a Complex I assembly factor associated with the MCIA complex (PMID:24344204). The study shows NDUFS2 co-purifies with assembly intermediates. The protein binding annotation captures the interaction with assembly factors during Complex I biogenesis. Reason: Generic 'protein binding' is uninformative. The relevant biology is Complex I assembly, already captured by the GO:0032981 annotation. NDUFS2 interacting with assembly factors is part of the normal assembly pathway, not a specific molecular function. |
| GO:0005515 protein binding | IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat... | MARK AS OVER ANNOTATED | Summary: IPI from a mitochondrial protein interaction mapping study (PMID:27499296). This is a high-throughput interaction screen identifying regulators of respiratory chain function. Reason: Generic 'protein binding' from a high-throughput interaction mapping study. Uninformative as a molecular function annotation for NDUFS2. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: IPI from a large-scale human interactome study (PMID:28514442). This is a high-throughput study mapping protein communities and disease networks. Reason: Generic 'protein binding' from a large-scale interactome study. Uninformative for understanding NDUFS2 molecular function. |
| GO:0005515 protein binding | IPI PMID:32807793 OSMR controls glioma stem cell respiration and confers resis... | MARK AS OVER ANNOTATED | Summary: IPI from a study showing OSMR interacts with NDUFS1/NDUFS2 of Complex I and promotes mitochondrial respiration in glioma stem cells (PMID:32807793). The study demonstrates a mitochondrial OSMR that interacts with NDUFS2 to regulate oxidative phosphorylation. Reason: While the OSMR-NDUFS2 interaction is an interesting finding, 'protein binding' is uninformative. The functional consequence (regulation of Complex I activity) is more relevant than the generic binding annotation. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IPI from a dual proteome-scale network study mapping cell-specific remodeling of the human interactome (PMID:33961781). High-throughput interaction data. Reason: Generic 'protein binding' from a large-scale interactome study. Uninformative for NDUFS2 function. |
| GO:0006120 mitochondrial electron transport, NADH to ubiquinone | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from Ensembl Compara orthology transfer. Consistent with the IBA and multiple experimental annotations for this core process. Reason: Correct, consistent with IBA and experimental evidence. Core process for NDUFS2. |
| GO:0019826 oxygen sensor activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IEA for oxygen sensor activity. This annotation reflects findings from Dunham-Snary et al. (PMID:30922174) showing NDUFS2 is essential for acute oxygen sensing in pulmonary vasculature. Supported by the IMP annotation from the same reference. Reason: Oxygen sensing is a tissue-specific function in pulmonary artery smooth muscle cells, not the core evolved function of NDUFS2. The primary role is as a Complex I catalytic subunit. The oxygen-sensing role appears to be a secondary consequence of the redox-sensitive [4Fe-4S] cluster and cysteine residues in NDUFS2, which are modified under hypoxic conditions. Keep as non-core. Supporting Evidence: PMID:30922174 Ndufs2 is essential for oxygen-sensing and HPV |
| GO:0022008 neurogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from Ensembl Compara orthology transfer for neurogenesis. Based on mouse model data (UniProt: By similarity) showing NDUFS2 is essential for neural stem and progenitor cell proliferation, differentiation and neuronal maturation. This is a downstream pleiotropic effect of Complex I deficiency, not a direct function. Reason: Neurogenesis is a downstream pleiotropic effect of Complex I function, not a direct function of NDUFS2. Complex I deficiency impairs mitochondrial energy production needed for neural development. This is not a core evolved function of the gene product. |
| GO:0032981 mitochondrial respiratory chain complex I assembly | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from Ensembl Compara for Complex I assembly. NDUFS2 is a core subunit of the Q-module that forms the initial nucleus of the peripheral arm junction with the membrane arm. Its methylation by NDUFAF7 at Arg-85 stabilizes the early 400 kDa assembly intermediate (PMID:24089531). Mutations in NDUFS2 affect assembly (PMID:14749350). Reason: NDUFS2 is essential for Complex I assembly as a structural core subunit, and its modification by NDUFAF7 is required for the assembly pathway. However, its role is primarily as a structural component that must be present for assembly to proceed, rather than having a specific assembly factor function. Assembly-related annotations for structural subunits are kept as non-core. Supporting Evidence: PMID:24089531 This methylation step occurs early in the assembly of complex I and probably stabilizes a 400-kDa subcomplex that forms the initial nucleus of the peripheral arm and its juncture with the membrane arm PMID:14749350 Our results show an important decrease in the levels of intact complex I in patients harboring mutations in nuclear-encoded complex I subunits, indicating that complex I assembly and/or stability is compromised |
| GO:0042063 gliogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from Ensembl Compara for gliogenesis. Based on mouse model data (UniProt: By similarity) showing NDUFS2 is essential for glia-like neural stem and progenitor cell proliferation and oligodendrocyte maturation. Reason: Gliogenesis is a downstream pleiotropic effect of Complex I function in neural tissue, not a direct function of NDUFS2. Energy metabolism is required for glial cell development, but this does not represent a specific molecular role of NDUFS2. |
| GO:0045271 respiratory chain complex I | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for Complex I localization, consistent with the IBA and multiple experimental annotations. Reason: Correct CC annotation, consistent with IBA and experimental evidence. Redundant but acceptable as an independent IEA. |
| GO:0061351 neural precursor cell proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from Ensembl Compara for neural precursor cell proliferation. Based on mouse model data. Like neurogenesis and gliogenesis, this is a downstream pleiotropic effect of mitochondrial energy metabolism. Reason: Neural precursor cell proliferation is a downstream pleiotropic effect of Complex I function, not a direct molecular function of NDUFS2. Keep as non-core. |
| GO:0071453 cellular response to oxygen levels | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IEA for cellular response to oxygen levels. Consistent with the IMP annotation from PMID:30922174 demonstrating NDUFS2's role in oxygen sensing. The IEA likely derives from the experimental annotation. Reason: Tissue-specific oxygen-sensing function in pulmonary vasculature, not a core evolved function. Keep as non-core, consistent with the oxygen sensor activity annotation. |
| GO:0003954 NADH dehydrogenase activity | IMP PMID:14749350 Differences in assembly or stability of complex I and other ... | ACCEPT | Summary: IMP annotation with 'contributes_to' qualifier from Ugalde et al. (PMID:14749350). The study used blue native electrophoresis to show that NDUFS2 mutations decrease levels of intact Complex I and Complex I activity, demonstrating that NDUFS2 contributes to NADH dehydrogenase activity. GO:0003954 (NADH dehydrogenase activity) is a broader parent of GO:0008137 (NADH dehydrogenase ubiquinone activity). Reason: Valid annotation. The study demonstrates that mutations in NDUFS2 result in decreased Complex I activity. The 'contributes_to' qualifier is appropriate. GO:0003954 is a parent term that captures the NADH dehydrogenase function; while GO:0008137 would be more specific, both are valid. Duplicates with the GO:0008137 annotations at different specificity levels are acceptable. Supporting Evidence: PMID:14749350 Our results show an important decrease in the levels of intact complex I in patients harboring mutations in nuclear-encoded complex I subunits, indicating that complex I assembly and/or stability is compromised |
| GO:0005743 mitochondrial inner membrane | IDA PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: IDA annotation from the cryo-EM megacomplex structure study (PMID:28844695). Guo et al. resolved the architecture of the human respiratory megacomplex I2III2IV2, directly visualizing NDUFS2 in the inner membrane Complex I structure. Reason: Direct structural evidence from cryo-EM confirms NDUFS2 localization to the mitochondrial inner membrane as part of Complex I. 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 a review on assembly of mammalian OXPHOS complexes (PMID:30030361). Complex I is the first enzyme of the mitochondrial respiratory chain, essential for aerobic respiration. NDUFS2 as a core subunit participates in this process. Reason: Valid broader process annotation. Complex I is essential for aerobic respiration, and NDUFS2 is a core catalytic subunit. The NAS evidence from a comprehensive review is appropriate. 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 the same OXPHOS assembly review (PMID:30030361). Complex I contributes to proton motive force generation, which drives ATP synthesis. However, NDUFS2 does not directly participate in the proton pumping or ATP synthesis. This is an indirect downstream consequence of Complex I activity. Reason: NDUFS2 contributes indirectly to proton motive force generation via its role in Complex I catalysis, but does not directly drive ATP synthesis. This is a downstream biological consequence rather than a core function of the gene product. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: HTP annotation from a quantitative human mitochondrial proteome study (PMID:34800366). Mass spectrometry confirmed NDUFS2 as a high-confidence mitochondrial protein. Reason: Correct CC annotation confirmed by high-throughput proteomics. The more specific annotations (inner membrane, Complex I) are also present. |
| 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. (PMID:11112787) showing that NDUFS2 mutations affect Complex I assembly patterns, demonstrated by monoclonal antibody analysis and sucrose gradient studies. The study examined patients with NDUFS2 mutations and showed altered Complex I subunit profiles. Reason: Valid experimental evidence. The study demonstrates that NDUFS2 mutations disrupt Complex I integrity, confirming NDUFS2 as a component of respiratory chain Complex I. Supporting Evidence: PMID:11112787 different mutations in the same gene are shown to give very similar subunit profiles |
| 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. (PMID:12611891) who immunopurified human NADH dehydrogenase and identified 42 subunits including NDUFS2 by mass spectrometry. Reason: Direct experimental identification of NDUFS2 as a subunit of immunopurified human Complex I by 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 | IDA PMID:17209039 Identification of mitochondrial complex I assembly intermedi... | ACCEPT | Summary: IDA annotation from Vogel et al. (PMID:17209039). The study traced NDUFS3-GFP assembly intermediates and identified NDUFS2-containing subcomplexes during Complex I biogenesis, confirming NDUFS2 as a Complex I component. Reason: Direct experimental evidence from assembly intermediate analysis confirming NDUFS2 in Complex I subcomplexes. Supporting Evidence: PMID:17209039 Upon induction, six distinct NDUFS3-GFP-containing subcomplexes gradually appeared on a blue native Western blot also observed in wild type HEK293 mitochondria |
| 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. (PMID:24746669) showing cyclin B1/Cdk1 phosphorylates Complex I subunits including NDUFS2, affecting CI function. The study confirms NDUFS2 as a Complex I subunit through functional phosphorylation studies. Reason: NDUFS2 is confirmed as a Complex I subunit that is functionally regulated by phosphorylation during the cell cycle. 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 | NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox... | ACCEPT | Summary: NAS annotation from Loeffen et al. (PMID:9878551) who completed cDNA characterization of all nuclear-encoded Complex I subunits, establishing NDUFS2 as a Complex I component. Reason: Early characterization study confirming NDUFS2 as a nuclear-encoded subunit of Complex I. Supporting Evidence: PMID:9878551 Now all currently known 41 proteins of human NADH:ubiquinone oxidoreductase have been characterized and reported in literature |
| GO:0008137 NADH dehydrogenase (ubiquinone) activity | IMP PMID:28031252 Compound heterozygosity for severe and hypomorphic NDUFS2 mu... | ACCEPT | Summary: IMP annotation from Gerber et al. (PMID:28031252). The study identified compound heterozygous NDUFS2 mutations (Tyr53Cys; Tyr308Cys) causing LHON-like optic neuropathy. In the yeast Yarrowia lipolytica ortholog NUCM, mutations resulted in moderate reduction of NADH-ubiquinone oxidoreductase activity. Reason: The study demonstrates that NDUFS2 mutations impair NADH dehydrogenase (ubiquinone) activity, confirming NDUFS2 contributes to this complex-level catalytic function. Note: the annotation lacks a 'contributes_to' qualifier which would be more appropriate for a complex subunit. Supporting Evidence: PMID:28031252 In the yeast Y. lipolytica ortholog NUCM, the mutations resulted in absence of complex I and moderate reduction in nicotinamide adenine dinucleotide-ubiquinone oxidoreductase activity, respectively |
| GO:0006120 mitochondrial electron transport, NADH to ubiquinone | IMP PMID:30922174 Ndufs2, a Core Subunit of Mitochondrial Complex I, Is Essent... | ACCEPT | Summary: IMP annotation from Dunham-Snary et al. (PMID:30922174). The study showed that siRNA knockdown of Ndufs2 in pulmonary artery smooth muscle cells decreases Complex I activity and impairs mitochondrial electron transport. Reason: Direct experimental evidence that NDUFS2 is required for mitochondrial electron transport from NADH to ubiquinone. Knockdown impairs Complex I-dependent respiration. Supporting Evidence: PMID:30922174 In PASMC, siNdufs2 (cells/tissue treated with Ndufs2 siRNA) decreased normoxic H2O2, prevented hypoxic increases in [Ca2+]i, and mimicked aspects of chronic hypoxia, including decreasing Complex I activity, elevating the nicotinamide adenine dinucleotide (NADH/NAD+) ratio and decreasing expression of the O2-sensitive ion channel, Kv1.5 |
| GO:0008137 NADH dehydrogenase (ubiquinone) activity | IMP PMID:22036843 A catalytic defect in mitochondrial respiratory chain comple... | ACCEPT | Summary: IMP with 'contributes_to' qualifier from Ngu et al. (PMID:22036843). The study showed that the NDUFS2 Asp446Asn mutation results in normal Complex I protein levels but strongly reduced catalytic activity, demonstrating a catalytic defect. The mutation resides near the coenzyme Q binding pocket. Reason: Key experimental evidence demonstrating that NDUFS2 directly contributes to Complex I catalytic function. The Asp446Asn mutation specifically impairs catalysis while maintaining complex assembly, showing NDUFS2's direct role in the enzymatic reaction. The 'contributes_to' qualifier is correct. Supporting Evidence: PMID:22036843 Complex I amounts in the patient carrying the Asp446Asn mutation were normal, while the complex I activity was strongly reduced, showing that the NDUFS2 mutation affects complex I enzymatic function ... We propose that the mutation interferes with the reduction of coenzyme Q or with the coupling of coenzyme Q reduction with the conformational changes involved in proton pumping of complex I |
| GO:0008137 NADH dehydrogenase (ubiquinone) activity | IMP PMID:30922174 Ndufs2, a Core Subunit of Mitochondrial Complex I, Is Essent... | ACCEPT | Summary: IMP with 'contributes_to' qualifier from Dunham-Snary et al. (PMID:30922174). siRNA knockdown of Ndufs2 decreased Complex I activity in pulmonary artery smooth muscle cells and caused functional inhibition of Complex I. Reason: Valid experimental evidence. siRNA knockdown of NDUFS2 causes functional inhibition of Complex I, confirming that NDUFS2 contributes to NADH dehydrogenase (ubiquinone) activity. The 'contributes_to' qualifier is correct. Supporting Evidence: PMID:30922174 Lung Ndufs2 cysteine residues became reduced during acute hypoxia and both hypoxia and reducing agents caused functional inhibition of Complex I |
| GO:0019826 oxygen sensor activity | IMP PMID:30922174 Ndufs2, a Core Subunit of Mitochondrial Complex I, Is Essent... | KEEP AS NON CORE | Summary: IMP annotation for oxygen sensor activity from Dunham-Snary et al. (PMID:30922174). The study demonstrates that NDUFS2, as the rotenone-binding site of Complex I, is essential for oxygen sensing in pulmonary vasculature. Hypoxia reduces NDUFS2 cysteine residues, causing functional inhibition of Complex I, decreasing H2O2 production, and triggering calcium signaling for vasoconstriction. Reason: The oxygen-sensing function is a tissue-specific (pulmonary artery smooth muscle cells) secondary consequence of NDUFS2's redox-sensitive properties. It is not the core evolved function of the gene product. The primary function is as a Complex I catalytic subunit. The oxygen-sensing mechanism exploits the redox chemistry of NDUFS2's cysteine residues and [4Fe-4S] cluster in a tissue-specific context. Notably, knockdown of other Complex I subunits (NDUFS1) or other proposed oxygen sensors (Rieske Fe-S center, COX4i2) had no effect on hypoxic calcium signaling, suggesting NDUFS2-specific involvement. Supporting Evidence: PMID:30922174 Ndufs2 is essential for oxygen-sensing and HPV PMID:30922174 Lung Ndufs2 cysteine residues became reduced during acute hypoxia and both hypoxia and reducing agents caused functional inhibition of Complex I |
| GO:0022008 neurogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation transferred from mouse ortholog by curator judgment. Based on mouse data showing NDUFS2 is essential for neural stem cell development (UniProt: By similarity). Reason: Downstream pleiotropic effect of Complex I deficiency on neural development. Not a direct molecular function. Keep as non-core, consistent with the IEA annotation. |
| GO:0032981 mitochondrial respiratory chain complex I assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for Complex I assembly transferred from ortholog. NDUFS2 is a core subunit required for proper Complex I assembly, as demonstrated by multiple studies showing that NDUFS2 mutations impair Complex I integrity (PMID:14749350, PMID:11112787). Reason: NDUFS2 is essential for Complex I assembly as a structural core subunit. However, the assembly role is secondary to its catalytic function. Keep as non-core. Supporting Evidence: PMID:14749350 a specific decrease of fully-assembled complex III in patients with mutations in NDUFS2 and NDUFS4 |
| GO:0042063 gliogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation transferred from mouse ortholog for gliogenesis. Downstream pleiotropic effect of Complex I function in neural tissue. Reason: Downstream pleiotropic effect, not a direct function. Consistent with IEA annotation. |
| GO:0061351 neural precursor cell proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation transferred from mouse ortholog for neural precursor cell proliferation. Downstream pleiotropic effect of mitochondrial energy metabolism. Reason: Downstream pleiotropic effect. Not a direct molecular function of NDUFS2. Consistent with the IEA annotation. |
| GO:0071453 cellular response to oxygen levels | IMP PMID:30922174 Ndufs2, a Core Subunit of Mitochondrial Complex I, Is Essent... | KEEP AS NON CORE | Summary: IMP annotation from Dunham-Snary et al. (PMID:30922174). The study shows that NDUFS2 in pulmonary artery smooth muscle cells responds to hypoxia via reduction of cysteine residues, leading to Complex I inhibition and downstream signaling. This is the process-level annotation corresponding to the oxygen sensor activity MF annotation. Reason: Tissue-specific oxygen-sensing function. The response to oxygen levels is a secondary consequence of NDUFS2's redox-sensitive properties in the pulmonary vasculature. Keep as non-core. Supporting Evidence: PMID:30922174 Lung Ndufs2 cysteine residues became reduced during acute hypoxia and both hypoxia and reducing agents caused functional inhibition of Complex I |
| GO:0042775 mitochondrial ATP synthesis coupled electron transport | IMP PMID:24746669 Cyclin B1/Cdk1 coordinates mitochondrial respiration for cel... | ACCEPT | Summary: IMP annotation from Wang et al. (PMID:24746669). The study showed that cyclin B1/Cdk1 phosphorylation of Complex I subunits including NDUFS2 enhances CI activity and increases ATP generation for G2/M cell cycle progression, demonstrating coupling between electron transport and ATP synthesis. Reason: Valid process annotation. Complex I activity is coupled to ATP synthesis via proton motive force generation, and this study demonstrates that phosphorylation of NDUFS2 and other CI subunits modulates this coupled process. Supporting Evidence: PMID:24746669 Mitochondria-targeted cyclin B1/Cdk1 increases mitochondrial respiration with enhanced oxygen consumption and ATP generation, which provides cells with efficient bioenergy for G2/M transition |
| GO:0005515 protein binding | IPI PMID:24089531 NDUFAF7 methylates arginine 85 in the NDUFS2 subunit of huma... | MARK AS OVER ANNOTATED | Summary: IPI annotation from Rhein et al. (PMID:24089531) showing NDUFS2 interacts with the methyltransferase NDUFAF7. NDUFAF7 symmetrically dimethylates Arg-85 in NDUFS2, a modification required for early Complex I assembly. This is a specific, functionally relevant interaction. Reason: While the NDUFS2-NDUFAF7 interaction is biologically important and well-characterized, 'protein binding' is uninformative. The functional consequence (methylation of Arg-85 for Complex I assembly) is more meaningful and is captured by assembly annotations. Supporting Evidence: PMID:24089531 it has been demonstrated that it is a protein methylase that symmetrically dimethylates the omega-N(G),N(G') atoms of residue Arg-85 in the NDUFS2 subunit of complex I |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-163217 | ACCEPT | Summary: TAS annotation from Reactome pathway for Complex I oxidation of NADH. NDUFS2 is a peripheral membrane protein on the matrix side of the inner membrane. UniProt confirms subcellular location as mitochondrion inner membrane, matrix side. Reason: Correct CC annotation. NDUFS2 is on the matrix-facing side of Complex I and participates in the matrix-arm catalytic reactions. The Reactome pathway correctly places NDUFS2 in the mitochondrial matrix context. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-6788523 | ACCEPT | Summary: TAS from Reactome pathway for NUBPL transfer of 4Fe-4S clusters to Complex I subunits. NDUFS2 receives its [4Fe-4S] cluster in the mitochondrial matrix during assembly. Reason: Correct CC annotation. The [4Fe-4S] cluster insertion into NDUFS2 occurs in the mitochondrial matrix. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-6799178 | ACCEPT | Summary: TAS from Reactome Complex I assembly pathway. NDUFS2 is part of assembly intermediates that form in the mitochondrial matrix. Reason: Correct CC annotation. Complex I assembly intermediates containing NDUFS2 are in the mitochondrial matrix. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-6799179 | ACCEPT | Summary: TAS from Reactome Complex I assembly pathway for peripheral arm subunit binding. Reason: Correct CC annotation, same rationale as other Reactome matrix annotations. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-6799191 | ACCEPT | Summary: TAS from Reactome for Intermediate 2 binding MT-ND1 subcomplex in the assembly pathway. Reason: Correct CC annotation. Assembly intermediates form in the matrix. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-6799196 | ACCEPT | Summary: TAS from Reactome for dissociation of assembly factors from the 980kDa complex to yield mature Complex I. Reason: Correct CC annotation. Final assembly steps occur at the matrix side of the inner membrane. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-6799197 | ACCEPT | Summary: TAS from Reactome for ND4/ND5 binding to the 550kDa assembly complex. Reason: Correct CC annotation for NDUFS2 participating in matrix-localized assembly. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-6799202 | ACCEPT | Summary: TAS from Reactome for the 315kDa and 370kDa subcomplexes combining to form the 550kDa complex during assembly. Reason: Correct CC annotation. Assembly intermediates in the matrix. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-6799203 | ACCEPT | Summary: TAS from Reactome for IP subcomplex binding NDUFAF3, NDUFAF4, TIMMDC1 to form Intermediate 1. NDUFS2 is part of the IP (iron-sulfur protein) subcomplex. Reason: Correct CC annotation. NDUFS2 is part of the IP subcomplex that assembles with factors in the matrix. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-6800868 | ACCEPT | Summary: TAS from Reactome for NDUF subunits binding to form the IP subcomplex. NDUFS2 is a core component of this initial assembly step. Reason: Correct CC annotation. The IP subcomplex containing NDUFS2 forms in the matrix. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:19725078 Proteomic analysis of increased Parkin expression and its in... | KEEP AS NON CORE | Summary: IPI annotation from Davison et al. (PMID:19725078) showing NDUFS2 was identified as a potential interactant of Parkin (an E3 ubiquitin ligase) by tandem affinity purification and mass spectrometry. Parkin is involved in modulation of mitochondrial function and Parkinson's disease. Reason: The interaction with Parkin suggests NDUFS2 may be a substrate or regulatory target of the ubiquitin-proteasome system in the context of mitochondrial quality control. This is more specific than generic 'protein binding' but represents a regulatory interaction rather than a core function. Keep as non-core. Supporting Evidence: PMID:19725078 Tandem affinity purification/MS revealed 14 potential interactants of Parkin; CKB, DBT, HSPD1, HSPA9, LRPPRC, NDUFS2, PRDX6, SLC25A5, TPI1, UCHL1, UQCRC1, VCL, YWHAZ, YWHAE |
| GO:0005515 protein binding | IPI PMID:20406883 MidA is a putative methyltransferase that is required for mi... | MARK AS OVER ANNOTATED | Summary: IPI from Carilla-Latorre et al. (PMID:20406883) showing that both Dictyostelium and human MidA (NDUFAF7) interact with the NDUFS2 subunit via yeast two-hybrid screening and pull-down experiments. Reason: Generic 'protein binding' is uninformative. The relevant interaction is with NDUFAF7 (MidA) methyltransferase for Complex I assembly. This functional role is captured by assembly annotations. Supporting Evidence: PMID:20406883 Using yeast two-hybrid screening and pull-down experiments, we showed that both proteins interact with the mitochondrial complex I subunit NDUFS2 |
| GO:0005515 protein binding | IPI PMID:19463981 Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66... | MARK AS OVER ANNOTATED | Summary: IPI from Saada et al. (PMID:19463981) showing NDUFAF3 interacts with Complex I subunits during assembly. NDUFS2 co-purifies with the assembly factor complex. Reason: Generic 'protein binding' is uninformative. The NDUFAF3 interaction is in the context of Complex I assembly, captured by the assembly annotations. Supporting Evidence: PMID:19463981 NDUFAF3 is a genuine mitochondrial complex I assembly protein that interacts with complex I subunits |
| GO:0005739 mitochondrion | IDA PMID:9585441 Mapping to 1q23 of the human gene (NDUFS2) encoding the 49-k... | ACCEPT | Summary: IDA annotation from Procaccio et al. (PMID:9585441) who mapped the NDUFS2 gene to chromosome 1q23 and performed immunodetection of the mature protein in mitochondria. Reason: Direct experimental evidence of NDUFS2 protein in mitochondria by immunodetection. An early but valid demonstration of mitochondrial localization. Supporting Evidence: PMID:9585441 Mapping to 1q23 of the human gene (NDUFS2) encoding the 49-kDa subunit of the mitochondrial respiratory Complex I and immunodetection of the mature protein in mitochondria |
| GO:0006120 mitochondrial electron transport, NADH to ubiquinone | NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox... | ACCEPT | Summary: NAS from Loeffen et al. (PMID:9878551) who completed cDNA characterization of nuclear-encoded Complex I subunits. The study establishes NDUFS2 as a subunit of the enzyme whose main function is electron transport from NADH to ubiquinone. Reason: Valid NAS annotation from an authoritative early characterization study. 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:0008137 NADH dehydrogenase (ubiquinone) activity | NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox... | ACCEPT | Summary: NAS from the same Loeffen et al. study (PMID:9878551) characterizing Complex I cDNAs. Reason: Valid NAS annotation from an authoritative characterization study. NDUFS2 is a core catalytic subunit of the NADH:ubiquinone oxidoreductase. |
| GO:0005739 mitochondrion | NAS PMID:9647766 cDNA sequence and chromosomal localization of the remaining ... | ACCEPT | Summary: NAS from Loeffen et al. (PMID:9647766) who completed cDNA cloning of the iron-sulfur protein subunits of Complex I including NDUFS2. Reason: Valid NAS annotation. The study establishes NDUFS2 as a mitochondrial protein. Supporting Evidence: PMID:9647766 NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial respiratory chain can be fragmented in a flavoprotein (FP), iron-sulfur protein (IP), and hydrophobic protein (HP) subfraction |
| GO:0006120 mitochondrial electron transport, NADH to ubiquinone | NAS PMID:9647766 cDNA sequence and chromosomal localization of the remaining ... | ACCEPT | Summary: NAS from Loeffen et al. (PMID:9647766). The study characterizes NDUFS2 as part of the iron-sulfur protein fraction of Complex I involved in electron transport. Reason: Valid NAS annotation from the original cDNA characterization study. |
| GO:0008137 NADH dehydrogenase (ubiquinone) activity | NAS PMID:9647766 cDNA sequence and chromosomal localization of the remaining ... | ACCEPT | Summary: NAS from Loeffen et al. (PMID:9647766) characterizing NDUFS2 as part of the NADH:ubiquinone oxidoreductase complex. Reason: Valid NAS annotation from the original characterization study. |
| GO:0009055 electron transfer activity | NAS PMID:9647766 cDNA sequence and chromosomal localization of the remaining ... | ACCEPT | Summary: NAS from Loeffen et al. (PMID:9647766). NDUFS2 is in the iron-sulfur protein (IP) fraction and contains a [4Fe-4S] cluster that participates in the electron relay chain within Complex I. The IP subfraction is significant because it contains important prosthetic groups highly conserved among species. Reason: Valid MF annotation, but not via an Fe-S cluster: the terminal N2 cluster is ligated by NDUFS7/PSST, not NDUFS2. NDUFS2 participates in electron transfer by forming the ubiquinone-binding channel that accepts electrons at the end of the Fe-S relay, which is a core molecular function of NDUFS2. Supporting Evidence: PMID:9647766 The IP subfraction is hypothesized to be significant, since it contains important prosthetic groups highly conserved among species |
| GO:0048039 ubiquinone binding | IDA PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | NEW | Summary: NDUFS2 directly forms the ubiquinone-binding channel with its conserved His59/Tyr108 residue pair contacting the quinone headgroup, as revealed by cryo-EM structures (PMID:28844695) and confirmed by molecular dynamics simulations and inhibitor binding studies. The Asp446Asn mutation near the Q-binding pocket specifically impairs catalysis without affecting complex assembly (PMID:22036843). This is a key molecular function not explicitly captured at the correct specificity in the existing annotation set (only the broader GO:0048038 quinone binding is present as IEA). Reason: Ubiquinone binding is a core molecular function of NDUFS2, directly supported by structural evidence showing NDUFS2 His59/Tyr108 form the Q-binding site and by mutational studies showing catalytic defects from Q-pocket mutations. This annotation adds specificity beyond the existing IEA for GO:0048038 (quinone binding). Note that the ubiquinone-specific term is safe for human NDUFS2 but not for the family as a whole: the family review (interpro/panther/PTHR11993/PTHR11993-review.yaml) finds the quinone-contacting His/Tyr pair invariant from Escherichia coli to plastid NdhH, so the acceptor-neutral GO:0048038 is the term that would be safe at family level, while GO:0048039 must stay inside the respiratory clade. Supporting Evidence: PMID:22036843 A 3-D model of the catalytic core of complex I showed that the mutated amino acid residue resides near the coenzyme Q binding pocket file:human/NDUFS2/NDUFS2-deep-research-falcon.md NDUFS2 lines the amphipathic Q-channel and contributes the conserved His/Tyr ligand pair (His59, Tyr108) that interacts with the quinone headgroup and small-molecule Q-site ligands |
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Download this section (compressed HTML)Q: Is the acute oxygen-sensing role of Ndufs2 in pulmonary artery smooth muscle, demonstrated in rat, conserved in human pulmonary vasculature, and does it depend on the same cysteine redox chemistry?
Q: What does NDUFAF7-mediated symmetric dimethylation of NDUFS2 Arg-85 do mechanistically - does it stabilise the nascent Q-module interface, gate the timing of assembly, or tune quinone-site chemistry in the mature enzyme?
Q: Why do some NDUFS2 mutations (for example Asp446Asn) produce a purely catalytic defect with normal holoenzyme levels while others reduce complex I abundance, and does this distinction predict clinical phenotype?
Q: Does the reported destabilisation of complex III in NDUFS2 patients reflect a genuine supercomplex-stabilising role for the NDUFS2-containing Q-module, or secondary turnover of unassembled complex III?
Experiment: Compare NDUFS2 knockout cells reconstituted with wild-type NDUFS2, with an Arg85-to-Lys methylation-null variant, and with NDUFAF7 knockout cells. Follow complex I assembly intermediates by complexome profiling over a time course after induction, and measure holoenzyme NADH:ubiquinone oxidoreductase activity and thermal stability, to separate an assembly-timing effect from a catalytic one.
Hypothesis: NDUFS2 Arg-85 dimethylation is required for stable formation of the Q-module nucleus rather than for catalysis by the mature enzyme.
Type: methylation-site mutagenesis with time-resolved complexome profiling
Experiment: Knock a panel of patient NDUFS2 variants (including Asp446Asn, Tyr53Cys and Tyr308Cys) into an isogenic human cell line and determine complex I structures by cryo-EM alongside measurement of holoenzyme levels, quinone-site kinetics with short-chain quinone analogues, and proton-pumping stoichiometry.
Hypothesis: Catalytic-defect and assembly-defect NDUFS2 variants act through distinct structural mechanisms at the quinone site.
Type: cryo-EM and kinetic analysis of a patient-variant allelic series
Experiment: In human pulmonary artery smooth muscle cells, deplete NDUFS2 and reconstitute with wild-type or cysteine-substituted NDUFS2, then measure mitochondrial and cytosolic hydrogen peroxide with targeted sensors, intracellular calcium responses to acute hypoxia, and Kv1.5 expression, using renal artery smooth muscle cells as the tissue-specificity control.
Hypothesis: Human NDUFS2 mediates acute hypoxic signalling in pulmonary artery smooth muscle.
Type: isoform-specific knockdown-rescue with redox and calcium imaging
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