NDUFB8 (Complex I-ASHI) is a nuclear-encoded accessory (supernumerary) subunit of the mitochondrial respiratory chain NADH:ubiquinone oxidoreductase (Complex I), the first and largest enzyme of the electron transport chain. Complex I couples oxidation of NADH and reduction of ubiquinone to translocation of protons across the mitochondrial inner membrane, generating the proton-motive force used for ATP synthesis. NDUFB8 is a stable structural subunit of the distal membrane arm (ND4/ND5 module) of the mature holoenzyme; it is a single-pass inner-membrane protein whose soluble domain faces the matrix, and it is not itself catalytic. As one of the 45 subunits of human Complex I, it is required for proper assembly and stability of a functional complex, and its loss destabilizes neighbouring subunits of the same structural module. Biallelic loss-of-function variants in NDUFB8 cause mitochondrial complex I deficiency (Leigh-like encephalomyopathy, MC1DN32). Its cleaved N-terminal mitochondrial targeting presequence directs import into mitochondria.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0045271 respiratory chain complex I | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically-inferred (IBA) membership of NDUFB8 in respiratory chain complex I. This is well supported: NDUFB8 is a conserved, stable accessory subunit of Complex I confirmed by biochemical purification and cryo-EM structures. Correct location/complex-membership annotation and a core aspect of the gene. |
| GO:0005739 mitochondrion | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO electronic annotation to mitochondrion. Correct but very general; the more specific and experimentally supported localization is the mitochondrial inner membrane / respiratory chain complex I. Kept as a true but non-core, redundant broad-localization annotation. |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic localization to mitochondrial inner membrane. This is correct: Complex I is embedded in the inner membrane and NDUFB8 is a single-pass inner-membrane protein with its soluble domain on the matrix side. This is a genuine core localization of the gene product. Supporting Evidence: file:human/NDUFB8/NDUFB8-uniprot.txt Mitochondrion inner membrane |
| GO:0006120 mitochondrial electron transport, NADH to ubiquinone | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO annotation of NDUFB8 to the core Complex I biological process, mitochondrial electron transport NADH to ubiquinone. As an accessory subunit NDUFB8 does not itself perform electron transfer, but it is required for assembly of a functional complex and so contributes to this process. Retained as a core biological-process annotation for the subunit. Supporting Evidence: PMID:9878551 transport of electrons from NADH to ubiquinone, which is |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Inter-ontology (GO:0008137 -> proton transmembrane transport) logical inference. The proton-motive force generated by Complex I is a real consequence of the complex activity, but this term is generic and derived from the (over-broad) direct assignment of NADH dehydrogenase activity to this accessory subunit. The subunit-appropriate BP is the more specific GO:0006120 (already annotated). Marked as over-annotated for this non-catalytic accessory subunit; the more specific complex-I-linked term (GO:0042776) captures the same biology. Supporting Evidence: PMID:9878551 accompanied by translocation of protons from the mitochondrial matrix to the |
| GO:0045271 respiratory chain complex I | IEA GO_REF:0000107 | ACCEPT | Summary: Complex I membership inferred by orthology (Ensembl Compara) from the mouse ortholog. Consistent with all direct/experimental evidence in human. Correct core complex-membership annotation. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: Direct (IDA, ComplexPortal) localization to the mitochondrial inner membrane, from the cryo-EM structure of the human respiratory megacomplex in which NDUFB8 is resolved as a Complex I subunit. Correct core localization. |
| GO:0009060 aerobic respiration | NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-... | KEEP AS NON CORE | Summary: NAS (ComplexPortal) annotation to aerobic respiration. True at the pathway level, since Complex I is the entry point of the electron transport chain, but this is a broad process term that reflects the whole OXPHOS system rather than the specific contribution of this subunit. Kept as a valid but non-core, general-process annotation; the subunit-specific process is captured by GO:0006120. Supporting Evidence: PMID:30030361 core proteins, performing the catalytic activities |
| 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 (ComplexPortal) annotation linking Complex I to proton motive force-driven ATP synthesis. Complex I contributes to the proton gradient that ultimately drives ATP synthase, so this is biologically defensible at the complex level, but it is downstream and process-level rather than the direct function of this accessory subunit. Kept as non-core. Supporting Evidence: file:human/NDUFB8/NDUFB8-uniprot.txt Complex I is composed of 45 different subunits. |
| GO:0045271 respiratory chain complex I | IPI PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: Direct physical-interaction (IPI, ComplexPortal) evidence for NDUFB8 as a component of respiratory chain complex I, from the cryo-EM megacomplex structure in which NDUFB8 is assigned as a Complex I subunit. Strong experimental support for core complex membership. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence (IDA) localizing NDUFB8 to mitochondrion. Correct but general; the specific localization (inner membrane / Complex I) is better captured elsewhere. Kept as non-core broad localization. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput (HTP) proteomic evidence for mitochondrial localization from a high-confidence human mitochondrial proteome study. Correct but general and redundant with the more specific inner-membrane/Complex I annotations. Kept as non-core. |
| GO:0045271 respiratory chain complex I | IDA PMID:12611891 The subunit composition of the human NADH dehydrogenase obta... | ACCEPT | Summary: Direct (IDA) evidence that NDUFB8 is a component of human Complex I, from one-step immunopurification of the intact NADH dehydrogenase followed by mass-spectrometric identification of the co-purifying subunits. Core complex-membership annotation with strong experimental support. Supporting Evidence: PMID:12611891 homologues of 42 polypeptides detected so far in the more extensively studied |
| GO:0045271 respiratory chain complex I | IMP PMID:19393246 Knockdown of human COX17 affects assembly and supramolecular... | ACCEPT | Summary: IMP (UniProt) annotation of Complex I membership. The cached abstract/title describes a study of COX17 knockdown and cytochrome c oxidase (Complex IV) supercomplex organization, so it is not obviously the canonical source for NDUFB8 Complex I membership; however this is an experimental (IMP) annotation whose full text I have not read, and the assigned term (respiratory chain complex I) is unambiguously correct biology for NDUFB8, which is independently established by the IDA/IPI/IBA annotations above. Per policy, an experimental annotation is not removed on the basis of an abstract-only cache; the term is accepted and deferred to the curator. |
| GO:0045271 respiratory chain complex I | IDA PMID:27626371 Accessory subunits are integral for assembly and function of... | ACCEPT | Summary: Direct (IDA) evidence for NDUFB8 as a Complex I subunit from the Stroud et al. systematic knockout/quantitative-proteomics study of the 45 human Complex I subunits. This is the UniProt FUNCTION reference and firmly establishes NDUFB8 as an accessory subunit required for assembly and stability of the complex. Core complex-membership annotation. Supporting Evidence: PMID:27626371 of each subunit affects the stability of other subunits residing in the same |
| GO:0045271 respiratory chain complex I | NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox... | ACCEPT | Summary: NAS annotation of Complex I membership from the cDNA characterization of the nuclear-encoded human Complex I subunits (which includes ASHI/NDUFB8). Correct; redundant with the stronger direct evidence but a legitimate core complex-membership annotation. Supporting Evidence: PMID:9878551 located in the inner mitochondrial membrane |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-8986181 | MARK AS OVER ANNOTATED | Summary: TAS (Reactome) localization to mitochondrial matrix. This derives from the mitochondrial protein-import pathway step (PITRM1 processing of targeting presequences), reflecting the transient matrix exposure of the imported precursor rather than the steady-state location of the mature protein. The mature NDUFB8 is an inner-membrane subunit with a matrix-facing soluble domain; a standalone matrix annotation mislocates the functional protein. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-163217 | ACCEPT | Summary: TAS (Reactome) localization to mitochondrial inner membrane, from the Complex I catalytic reaction event. Correct core localization for this inner-membrane Complex I subunit; redundant with the IDA/IEA inner-membrane annotations. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799178 | ACCEPT | Summary: TAS (Reactome) inner-membrane localization from a Complex I biogenesis (assembly intermediate) event. Correct localization; redundant with other inner-membrane annotations. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799179 | ACCEPT | Summary: TAS (Reactome) inner-membrane localization from a Complex I biogenesis event. Correct localization; redundant with other inner-membrane annotations. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799191 | ACCEPT | Summary: TAS (Reactome) inner-membrane localization from a Complex I biogenesis event. Correct localization; redundant with other inner-membrane annotations. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799196 | ACCEPT | Summary: TAS (Reactome) inner-membrane localization from a Complex I biogenesis event (dissociation of assembly factors to yield mature Complex I). Correct localization; redundant with other inner-membrane annotations. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799197 | ACCEPT | Summary: TAS (Reactome) inner-membrane localization from a Complex I biogenesis event. Correct localization; redundant with other inner-membrane annotations. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799202 | ACCEPT | Summary: TAS (Reactome) inner-membrane localization from a Complex I biogenesis event. Correct localization; redundant with other inner-membrane annotations. |
| 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 to the core Complex I process, mitochondrial electron transport NADH to ubiquinone, from the cDNA characterization paper. As a required structural subunit of the complex NDUFB8 contributes to this process. This is the subunit-appropriate core biological process and is accepted. Supporting Evidence: PMID:9878551 transport of electrons from NADH to ubiquinone, which is |
| GO:0008137 NADH dehydrogenase (ubiquinone) activity | NAS PMID:9878551 cDNA of eight nuclear encoded subunits of NADH:ubiquinone ox... | MARK AS OVER ANNOTATED | Summary: NAS annotation directly assigning NADH dehydrogenase (ubiquinone) activity to NDUFB8 with the "enables" qualifier. This is an over-annotation for this subunit: NDUFB8 is an accessory/supernumerary subunit that is explicitly "believed not to be involved in catalysis" (UniProt); the catalytic NADH dehydrogenase activity is a property of the whole complex (driven by the 14 conserved core subunits and their cofactors), not of this single subunit. NDUFB8 contributes to this complex-level activity structurally but does not independently enable it, so the direct "enables" assignment should be demoted (captured via contributes_to_molecular_function in core_functions). Supporting Evidence: file:human/NDUFB8/NDUFB8-uniprot.txt chain NADH dehydrogenase (Complex I), that is believed not to be |
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Download this section (compressed HTML)Q: Beyond its structural role, does NDUFB8 contribute to regulation of Complex I activity, stability, or turnover (e.g. under oxidative stress), or is its function purely as a scaffold component of the membrane arm?
Q: Do the disease-associated NDUFB8 variants (MC1DN32) act purely by destabilizing the assembled complex, or do any perturb membrane-arm assembly intermediates specifically?
Experiment: Quantitative complexome profiling (BN-PAGE/mass spectrometry) of NDUFB8 knockout versus wild-type cells to define which Complex I subassembly intermediates accumulate and which neighbouring subunits are destabilized.
Experiment: Structure-guided assessment of MC1DN32 missense variants (e.g. by cryo-EM or stability assays of a reconstituted membrane-arm module) to distinguish assembly defects from steady-state complex destabilization.
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