NDUFC2 (B14.5b; CI-B14.5b) is a small (119 aa), nuclear-encoded, single-pass membrane protein that is an accessory (supernumerary) subunit of the membrane arm of mitochondrial respiratory Complex I (NADH:ubiquinone oxidoreductase). It is a stable structural component of the mature holoenzyme rather than a catalytic subunit: it is not itself involved in electron transfer but is required for correct assembly and stability of the complex, particularly the ND2 module of the membrane arm. NDUFC2 localizes to the mitochondrial inner membrane with its N- and C-terminal regions on the matrix side, and interacts with the assembly-associated membrane protein TMEM242. Loss of Complex I function through defective assembly reduces mitochondrial NADH-driven electron transport and proton pumping; bi-allelic pathogenic NDUFC2 variants cause an autosomal-recessive mitochondrial Complex I deficiency (nuclear type 36, MC1DN36) presenting as early-onset Leigh syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0045271 respiratory chain complex I | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assertion that NDUFC2 is part_of respiratory chain complex I. This is the well-established core cellular-component role of the protein: NDUFC2/B14.5b is a genuine structural subunit of the Complex I holoenzyme, corroborated by immunocapture/MS, cryo-EM and complexome profiling. Supporting Evidence: file:human/NDUFC2/NDUFC2-uniprot.txt Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (IEA) mitochondrial inner membrane localization. This is correct and matches the experimentally supported UniProt subcellular location; NDUFC2 is a single-pass inner-membrane protein sitting in the Complex I membrane arm. Supporting Evidence: file:human/NDUFC2/NDUFC2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0006120 mitochondrial electron transport, NADH to ubiquinone | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO (IEA) mapping of the NDUFC2 family to the Complex I electron transport process. NDUFC2 does not itself carry electrons, but as an integral structural subunit of Complex I it is legitimately involved in the holoenzyme process of mitochondrial NADH-to-ubiquinone electron transport. Retained as a core biological-process term. Supporting Evidence: file:human/NDUFC2/NDUFC2-uniprot.txt Complex I functions in the transfer of electrons from NADH to the respiratory chain. |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Inter-ontology (GO_REF:0000108) inference from the catalytic MF GO:0008137. Complex I couples electron transfer to proton translocation across the inner membrane, so the holoenzyme is involved in proton transport; however this is a property of the pumping (membrane/ND) core modules and is a fairly general term for a non-catalytic accessory subunit. Keep as a non-core process annotation. Supporting Evidence: PMID:9878551 translocation of protons from the mitochondrial matrix to the intermembrane space |
| GO:0010918 positive regulation of mitochondrial membrane potential | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic annotation transferred from a rat ortholog (Ensembl Compara). A raised/maintained mitochondrial membrane potential is a downstream physiological consequence of a functional respiratory chain, not a direct molecular role of this accessory structural subunit. Over-annotation. |
| GO:0032981 mitochondrial respiratory chain complex I assembly | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic (Ensembl ortholog) assignment of Complex I assembly. This is correct and is in fact one of the core, experimentally supported functions of NDUFC2 (see the IMP annotation from PMID:32969598): NDUFC2 is required for assembly of the membrane arm, particularly the ND2 module. Supporting Evidence: file:human/NDUFC2/NDUFC2-uniprot.txt believed not to be involved in catalysis but required for the complex assembly |
| GO:0045271 respiratory chain complex I | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic (Ensembl ortholog) part_of respiratory chain complex I. Redundant with the IBA/IDA/IPI annotations to the same term and correct; NDUFC2 is a structural subunit of the holoenzyme. Supporting Evidence: file:human/NDUFC2/NDUFC2-uniprot.txt Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) |
| GO:1901223 negative regulation of non-canonical NF-kappaB signal transduction | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic annotation transferred from a rat ortholog. There is no evidence that NDUFC2 acts as a regulator of NF-kappaB signaling; this is a pleiotropic/indirect inference far removed from the protein's role as a Complex I structural subunit. Over-annotation. |
| GO:1903427 negative regulation of reactive oxygen species biosynthetic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic annotation transferred from a rat ortholog. ROS production is a side-effect of Complex I electron transport; modulation of ROS is an indirect downstream consequence rather than a direct molecular function of this accessory subunit. Over-annotation. |
| GO:2001171 positive regulation of ATP biosynthetic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic annotation transferred from a rat ortholog. ATP synthesis is an OXPHOS-system-level output downstream of a functional respiratory chain; casting NDUFC2 as a positive regulator of ATP biosynthesis is an indirect over-annotation for a non-catalytic Complex I structural subunit. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: Experimental (IDA, ComplexPortal) mitochondrial inner membrane localization, supported by cryo-EM of the human respiratory megacomplex that assigns individual CI subunits (including NDUFC2, PDB chain g) within the membrane arm. Correct core localization. Supporting Evidence: file:human/NDUFC2/NDUFC2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0009060 aerobic respiration | NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-... | KEEP AS NON CORE | Summary: Non-traceable-author (NAS, ComplexPortal) involvement in aerobic respiration. As a subunit of Complex I, the first enzyme of the respiratory chain, NDUFC2 participates in aerobic respiration, but this is a very general process term; the more specific GO:0006120 (electron transport, NADH to ubiquinone) captures its role better. Keep as non-core. Supporting Evidence: file:human/NDUFC2/NDUFC2-uniprot.txt Complex I functions in the transfer of electrons from NADH to the respiratory chain. |
| GO:0042776 proton motive force-driven mitochondrial ATP synthesis | NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-... | MARK AS OVER ANNOTATED | Summary: NAS (ComplexPortal) involvement in proton-motive-force-driven ATP synthesis. ATP synthesis is carried out by Complex V (ATP synthase); Complex I only contributes upstream to the proton gradient. Assigning the ATP-synthesis process directly to a Complex I accessory subunit conflates distinct complexes and is an over-annotation. |
| GO:0045271 respiratory chain complex I | IPI PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: Experimental (IPI, ComplexPortal) part_of respiratory chain complex I from the cryo-EM megacomplex structure. This directly establishes NDUFC2 as a structural member of the assembled Complex I. Core annotation. Supporting Evidence: file:human/NDUFC2/NDUFC2-uniprot.txt Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput (HTP) mitochondrial localization from a quantitative human mitochondrial proteome study. Correct but less specific than the inner-membrane annotations; retained as a broader, non-core localization. Supporting Evidence: file:human/NDUFC2/NDUFC2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0045271 respiratory chain complex I | IDA PMID:12611891 The subunit composition of the human NADH dehydrogenase obta... | ACCEPT | Summary: Experimental (IDA) part_of respiratory chain complex I from one-step immunopurification and MS identification of the human Complex I subunit set, in which NDUFC2/B14.5b was identified. Directly supports complex membership; core 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 | IDA PMID:27626371 Accessory subunits are integral for assembly and function of... | ACCEPT | Summary: Experimental (IDA) part_of respiratory chain complex I from the Stroud et al. gene-editing study of accessory subunits, which established the accessory subunit set (including NDUFC2) as integral to assembly and function of human Complex I. Core annotation. Supporting Evidence: PMID:27626371 Accessory subunits are integral for assembly and function of human mitochondrial complex I. |
| GO:0045271 respiratory chain complex I | NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox... | ACCEPT | Summary: NAS part_of respiratory chain complex I from the cDNA characterization of nuclear-encoded Complex I subunits. Correct complex membership, though redundant with the stronger experimental IDA/IPI annotations to the same term. Supporting Evidence: PMID:9878551 all currently known 41 proteins of human NADH:ubiquinone oxidoreductase have been characterized |
| GO:0005515 protein binding | IPI PMID:33753518 TMEM70 and TMEM242 help to assemble the rotor ring of human ... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation capturing the physical interaction of NDUFC2 with the membrane protein TMEM242 (UniProtKB:Q9NWH2). The interaction is genuine and documented (NDUFC2 co-purifies with TMEM242 among the membrane-arm complex I subunits), but the bare "protein binding" term is uninformative about molecular function. Kept but flagged as over-annotated; the biologically meaningful role is structural/assembly. Supporting Evidence: PMID:33753518 TMEM242-t was also bound to TMEM70 and, to a lesser extent, to subunit c and to the NDUFC2, ND2, and ND3 membrane subunits of complex I |
| GO:0005515 protein binding | IPI PMID:32320651 Dissecting the Roles of Mitochondrial Complex I Intermediate... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation to COA1 (UniProtKB:Q9GZY4) from a study of MCIA-complex assembly factors of the ND2 membrane module, consistent with NDUFC2's location in the same membrane-arm module. The interaction is plausible but the bare "protein binding" term is uninformative; flagged as over-annotated rather than removed (experimental IPI). |
| GO:0032981 mitochondrial respiratory chain complex I assembly | IMP PMID:32969598 Bi-allelic pathogenic variants in NDUFC2 cause early-onset L... | ACCEPT | Summary: Experimental (IMP) involvement in Complex I assembly, from patients with bi-allelic NDUFC2 variants (Leigh syndrome, MC1DN36). Complexome profiling showed loss of NDUFC2 causes defective assembly with stalled biogenesis intermediates, and wild-type cDNA rescued assembly. This is a core, strongly supported function of NDUFC2 (assembly of the membrane arm / ND2 module). Supporting Evidence: PMID:32969598 indicating a crucial role for NDUFC2 in the assembly of the membrane arm of complex I, particularly the ND2 module |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6798739 | MARK AS OVER ANNOTATED | Summary: Reactome (TAS) plasma membrane localization arising from a neutrophil degranulation ("Exocytosis of azurophil granule membrane proteins") pathway. NDUFC2 is a bona fide mitochondrial inner-membrane Complex I subunit; a plasma-membrane location is not supported and reflects bulk-pathway over-inclusion. Over-annotation. |
| GO:0035577 azurophil granule membrane | TAS Reactome:R-HSA-6798739 | MARK AS OVER ANNOTATED | Summary: Reactome (TAS) azurophil granule membrane localization from the same neutrophil degranulation pathway. Azurophil (primary) granules are myeloperoxidase-rich secretory granules; placing a mitochondrial Complex I subunit there is biologically implausible and reflects pathway over-inclusion. Over-annotation. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-163217 | ACCEPT | Summary: Reactome (TAS) mitochondrial inner membrane localization from the Complex I catalytic reaction event. Correct core localization; redundant with the experimental IDA annotations. Supporting Evidence: file:human/NDUFC2/NDUFC2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799178 | ACCEPT | Summary: Reactome (TAS) mitochondrial inner membrane localization from a Complex I biogenesis step. Correct core localization; redundant with experimental annotations to the same term. Supporting Evidence: file:human/NDUFC2/NDUFC2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799179 | ACCEPT | Summary: Reactome (TAS) mitochondrial inner membrane localization from a Complex I biogenesis step. Correct core localization; redundant. Supporting Evidence: file:human/NDUFC2/NDUFC2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799191 | ACCEPT | Summary: Reactome (TAS) mitochondrial inner membrane localization from a Complex I biogenesis step. Correct core localization; redundant. Supporting Evidence: file:human/NDUFC2/NDUFC2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799196 | ACCEPT | Summary: Reactome (TAS) mitochondrial inner membrane localization from a Complex I biogenesis step. Correct core localization; redundant. Supporting Evidence: file:human/NDUFC2/NDUFC2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799197 | ACCEPT | Summary: Reactome (TAS) mitochondrial inner membrane localization from a Complex I biogenesis step. Correct core localization; redundant. Supporting Evidence: file:human/NDUFC2/NDUFC2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799202 | ACCEPT | Summary: Reactome (TAS) mitochondrial inner membrane localization from a Complex I biogenesis step. Correct core localization; redundant. Supporting Evidence: file:human/NDUFC2/NDUFC2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005737 cytoplasm | IDA GO_REF:0000054 | MARK AS OVER ANNOTATED | Summary: IDA cytoplasm localization from a LIFEdb fluorescent fusion-protein screen. For a mitochondrial inner-membrane protein, a generic "cytoplasm" call most likely reflects mistargeting/overexpression artefact of the GFP-fusion and is far less informative than the mitochondrial annotations. Over-annotation. |
| GO:0006120 mitochondrial electron transport, NADH to ubiquinone | NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox... | ACCEPT | Summary: NAS involvement in mitochondrial NADH-to-ubiquinone electron transport from the Complex I cDNA characterization paper. NDUFC2 does not itself transfer electrons but is a structural subunit of the holoenzyme that performs this process; retained as a core biological-process annotation. Supporting Evidence: PMID:9878551 Its main function is the transport of electrons from NADH to ubiquinone |
| GO:0008137 NADH dehydrogenase (ubiquinone) activity | NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox... | MODIFY | Summary: NAS annotation asserting that NDUFC2 enables NADH dehydrogenase (ubiquinone) activity. NDUFC2 is explicitly non-catalytic; the NADH:ubiquinone oxidoreductase activity is a property of the assembled holoenzyme to which NDUFC2 contributes structurally, not one it directly enables. The catalytic activity resides in the NDUFV/NDUFS core subunits. MODIFY so the catalytic MF is expressed as a contributes_to relationship (see core_functions) rather than a direct enables; the honest per-protein MF is structural molecule activity. Proposed replacements: structural molecule activity Supporting Evidence: file:human/NDUFC2/NDUFC2-uniprot.txt believed not to be involved in catalysis but required for the complex assembly |
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Download this section (compressed HTML)Q: Does NDUFC2 have any moonlighting role outside Complex I, or is the reported "Human lung cancer oncogene 1 (HLC-1)" activity entirely attributable to its Complex I / mitochondrial function?
Q: What is the functional significance, if any, of the NDUFC2-KCTD14 read-through fusion isoform relative to canonical NDUFC2?
Experiment: Structural or crosslinking analysis to map the precise interfaces by which NDUFC2/B14.5b stabilizes the ND2 module of the Complex I membrane arm.
Experiment: Rescue of NDUFC2-null cells with catalytically neutral point mutants to define which residues are required for Complex I assembly versus stability.
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