NDUFA13 (also known as GRIM-19 and Complex I-B16.6) is a 144-residue, ~16.7 kDa nuclear-encoded accessory ("supernumerary") subunit of the peripheral/matrix arm of mitochondrial Complex I (NADH:ubiquinone oxidoreductase, the first enzyme of the respiratory electron transport chain). It is a genuine, stable structural component of the mature holoenzyme but does not itself catalyze NADH oxidation, quinone reduction, or proton translocation; instead it stabilizes the complex and is strictly required for its assembly and electron-transfer activity, so its loss causes Complex I instability and mitochondrial disease. NDUFA13 anchors to the inner mitochondrial membrane on the matrix side via a single transmembrane helix. In addition to this structural role, NDUFA13/GRIM-19 has a well-documented moonlighting function in cell-death regulation: it was originally isolated as a mediator of interferon-beta/retinoic-acid-induced tumor-cell death and is a specific negative regulator of the transcription factor STAT3, binding the STAT3 transactivation domain and repressing STAT3-dependent transcription. It also associates with the mitochondrial serine protease HtrA2/OMI to promote apoptosis, acts as a chaperone that recruits STAT3 into mitochondria and integrates it into Complex I, and interacts with NOD2/CARD15 in innate immune signaling. A small pool localizes to the nucleus and cytoplasm, particularly upon interferon/retinoic-acid treatment.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0045271 respiratory chain complex I | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference of Complex I membership. Correct: NDUFA13 is a bona fide accessory subunit of respiratory chain complex I, corroborated by direct experimental identification of the protein in immunopurified human Complex I. This is a core structural aspect of the gene. Supporting Evidence: PMID:12611891 These polypeptides include the GRIM-19 protein |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic SubCell mapping of the UniProt Nucleus annotation. This is a real but secondary (moonlighting-associated) localization: a GRIM-19 pool is nuclear, particularly upon IFN/RA treatment. Duplicates the experimental EXP nucleus annotation (PMID:12628925). Keep, but as non-core since the core function is in the mitochondrion. Supporting Evidence: PMID:10924506 GRIM-19 is primarily a nuclear protein |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (IEA) inner-membrane localization. Correct and core: NDUFA13 is a single-pass inner-membrane protein (matrix side) that is part of membrane-arm- anchored Complex I. Strongly supported by multiple experimental annotations. Supporting Evidence: file:human/NDUFA13/NDUFA13-uniprot.txt Mitochondrion inner membrane |
| GO:0005515 protein binding | IPI PMID:15753091 GRIM-19 interacts with nucleotide oligomerization domain 2 a... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" (IPI) from the NOD2/CARD15 interaction. The interaction itself is biologically meaningful (GRIM-19 is required for NOD2-mediated NF-kB activation in intestinal epithelium), but GO:0005515 is uninformative as a molecular function. Per policy, retained rather than removed, but flagged as an over-annotation; the meaningful biology is a non-core innate-immunity role. Supporting Evidence: PMID:15753091 interacts with endogenous NOD2 |
| GO:0005515 protein binding | IPI PMID:17297443 GRIM-19 associates with the serine protease HtrA2 for promot... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" (IPI) from the HtrA2/OMI interaction. The interaction is genuine and functionally important (GRIM-19 associates with HtrA2 to augment IFN/RA-dependent apoptosis and XIAP destruction), but GO:0005515 conveys no specific molecular function. Retained per policy but marked over-annotated; the meaningful role is captured in the apoptosis annotations below. Supporting Evidence: PMID:17297443 GRIM-19 physically interacts with HtrA2 |
| GO:0005515 protein binding | IPI PMID:17500595 Huntingtin interacting proteins are genetic modifiers of neu... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" (IPI) with huntingtin (HTT) from a large-scale huntingtin-interacting-protein screen. Uninformative as a molecular function and of uncertain physiological relevance for NDUFA13. Retained per policy, flagged as over-annotation. |
| GO:0005515 protein binding | IPI PMID:31617661 Global Interactome Mapping of Mitochondrial Intermembrane Sp... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" (IPI) with HTRA2 from a high-throughput interactome map of mitochondrial intermembrane-space proteases. Consistent with the HtrA2 association but uninformative as an MF. Retained per policy, flagged as over-annotation. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" (IPI) with HTT from a large-scale interactome/aggregation map of neurodegenerative-disease proteins. Uninformative as a molecular function and of uncertain relevance to NDUFA13's biology. Retained per policy, flagged as over-annotation. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" (IPI) with HTRA2 from a multimodal cell-map / structural genomics interactome. Uninformative as an MF. Retained per policy, flagged as over-annotation. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (IEA) mitochondrial localization. Correct and core, though coarse relative to the more specific inner-membrane/Complex I annotations. Extensively supported by experimental evidence. Supporting Evidence: PMID:15367666 its primary localization in the mitochondria |
| GO:0045271 respiratory chain complex I | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (IEA) Complex I membership, redundant with the experimental IDA/IMP and IBA annotations. Core structural aspect. Accept. Supporting Evidence: PMID:27626371 Accessory subunits are integral for assembly and function of human |
| GO:0005743 mitochondrial inner membrane | IDA PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: Direct (IDA, ComplexPortal) inner-membrane localization of NDUFA13 from cryo-EM of the human respiratory megacomplex, which precisely assigns individual Complex I subunits within the inner membrane. Core mitochondrial localization. Accept. Supporting Evidence: PMID:28844695 precise assignment of individual subunits of |
| GO:0009060 aerobic respiration | NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-... | KEEP AS NON CORE | Summary: Complex-level aerobic-respiration BP asserted (NAS, ComplexPortal) for the Complex I subunit. True at the holoenzyme level but high/general; more specific to NDUFA13's role is mitochondrial electron transport (NADH to ubiquinone). Keep as a non-core, complex-level process annotation. Supporting Evidence: PMID:30030361 performing the catalytic activities |
| GO:0042776 proton motive force-driven mitochondrial ATP synthesis | NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-... | MARK AS OVER ANNOTATED | Summary: Complex-level BP (NAS, ComplexPortal). Complex I contributes to the proton gradient that drives ATP synthesis, but ATP synthesis itself is performed by Complex V, and NDUFA13 is a non-catalytic accessory subunit. This is an over-annotation at the level of the individual subunit. |
| GO:0045271 respiratory chain complex I | IPI PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ... | ACCEPT | Summary: ComplexPortal IPI assignment of NDUFA13 to Complex I from the human megacomplex cryo-EM structure. Duplicates the IDA membership annotation. Core structural aspect. Accept. Supporting Evidence: PMID:28844695 precise assignment of individual subunits of |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence-based (HPA) mitochondrial localization. Correct and core, consistent with all other evidence. Coarser than inner-membrane/Complex I. Accept. |
| GO:0005634 nucleus | EXP PMID:12628925 GRIM-19, a death-regulatory gene product, suppresses Stat3 a... | KEEP AS NON CORE | Summary: Experimental nuclear localization. GRIM-19 has a documented nuclear pool (and was originally described as primarily nuclear), associated with its moonlighting STAT3/cell-death role. Genuine but non-core relative to the mitochondrial structural function. Supporting Evidence: PMID:10924506 GRIM-19 is primarily a nuclear protein |
| GO:0005743 mitochondrial inner membrane | EXP PMID:12628925 GRIM-19, a death-regulatory gene product, suppresses Stat3 a... | ACCEPT | Summary: Experimental inner-membrane localization. Core: NDUFA13 co-localizes with mitochondrial markers and is an inner-membrane Complex I subunit. Accept. Supporting Evidence: PMID:12628925 co-localizes with mitochondrial |
| GO:0005743 mitochondrial inner membrane | EXP PMID:15059901 GW112, a novel antiapoptotic protein that promotes tumor gro... | ACCEPT | Summary: Experimental inner-membrane localization (from the OLFM4/GW112 study, which also examined GRIM-19 localization). Core mitochondrial localization. Accept. |
| GO:0005743 mitochondrial inner membrane | EXP PMID:15367666 GRIM-19, a cell death regulatory protein, is essential for a... | ACCEPT | Summary: Experimental inner-membrane / mitochondrial localization from the study showing GRIM-19 is a functional Complex I component essential for assembly. Core. Accept. Supporting Evidence: PMID:15367666 its primary localization in the mitochondria |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput mitochondrial-proteome localization. Correct and core, coarse relative to inner-membrane/Complex I annotations. Accept. |
| GO:0045271 respiratory chain complex I | IDA PMID:12611891 The subunit composition of the human NADH dehydrogenase obta... | ACCEPT | Summary: Direct experimental identification (mass spectrometry of immunopurified human NADH dehydrogenase) of GRIM-19 as a Complex I subunit. This is a key primary demonstration of Complex I membership and a core structural aspect. Accept. Supporting Evidence: PMID:12611891 These polypeptides include the GRIM-19 protein |
| GO:0045271 respiratory chain complex I | IDA PMID:17209039 Identification of mitochondrial complex I assembly intermedi... | ACCEPT | Summary: Direct identification of NDUFA13 in Complex I / assembly-intermediate analysis (NDUFS3-tracing study). Core structural aspect of Complex I membership. Accept. |
| GO:0045271 respiratory chain complex I | IMP PMID:25901006 Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, d... | ACCEPT | Summary: Complex I membership supported by mutational/patient evidence: the germline R57H mutation reduces NDUFA13 protein and causes Complex I instability, showing NDUFA13 is an integral component of the holoenzyme. Core. Accept. Supporting Evidence: PMID:25901006 the abundances of NDUFA13 protein, CI holoenzyme and super complexes were drastically reduced |
| GO:0045271 respiratory chain complex I | IDA PMID:27626371 Accessory subunits are integral for assembly and function of... | ACCEPT | Summary: Direct identification of NDUFA13 as an integral accessory subunit of human Complex I via CRISPR-knockout + quantitative proteomics. Primary support for Complex I membership. Core. Accept. Supporting Evidence: PMID:27626371 25 subunits are strictly required for assembly of a functional complex |
| GO:0045732 positive regulation of protein catabolic process | IGI PMID:17297443 GRIM-19 associates with the serine protease HtrA2 for promot... | KEEP AS NON CORE | Summary: GRIM-19 augments HtrA2-driven destruction of the antiapoptotic protein XIAP, i.e. positively regulates protein catabolism in the apoptotic context. A genuine moonlighting (apoptosis) function. Keep as non-core. Supporting Evidence: PMID:17297443 the HtrA2-driven destruction of the antiapoptotic protein X-linked inhibitor of apoptosis (XIAP) is augmented |
| GO:0061133 endopeptidase activator activity | IC PMID:17297443 GRIM-19 associates with the serine protease HtrA2 for promot... | KEEP AS NON CORE | Summary: Curator-inferred (IC, from the positive regulation of protein catabolism) MF: GRIM-19 augments the serine-protease HtrA2's destruction of XIAP. Reflects the moonlighting HtrA2/apoptosis axis rather than the core Complex I structural role. Retained as a non-core moonlighting molecular function. Supporting Evidence: PMID:17297443 GRIM-19 physically interacts with HtrA2 and augments cell death |
| GO:1900119 positive regulation of execution phase of apoptosis | IGI PMID:17297443 GRIM-19 associates with the serine protease HtrA2 for promot... | KEEP AS NON CORE | Summary: GRIM-19 promotes IFN/RA-dependent cell death via its HtrA2 interaction. This is the well-documented pro-apoptotic moonlighting function for which GRIM-19 was originally discovered. Genuine but non-core relative to the Complex I structural role. Keep as non-core. Supporting Evidence: PMID:17297443 augments cell death in an IFN/all-trans retinoic acid (RA)-dependent manner |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9839110 | ACCEPT | Summary: Reactome (TAS) inner-membrane localization. Correct and core. Accept. |
| GO:0032981 mitochondrial respiratory chain complex I assembly | IMP PMID:25901006 Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, d... | ACCEPT | Summary: NDUFA13 is required for Complex I assembly/stability: loss (patient R57H mutation or silencing) causes CI instability with reduced holoenzyme and supercomplex. This is a core biological process for the gene. Accept. Supporting Evidence: PMID:25901006 induces CI instability |
| GO:0035458 cellular response to interferon-beta | IDA PMID:17297443 GRIM-19 associates with the serine protease HtrA2 for promot... | KEEP AS NON CORE | Summary: GRIM-19 is an IFN-beta/retinoic-acid-induced gene product mediating the cellular response to IFN-beta in the cell-death pathway. Genuine moonlighting function; non-core relative to the structural Complex I role. Keep as non-core. Supporting Evidence: PMID:17297443 novel interferon (IFN)-retinoid regulated cell death |
| GO:0071300 cellular response to retinoic acid | IDA PMID:17297443 GRIM-19 associates with the serine protease HtrA2 for promot... | KEEP AS NON CORE | Summary: GRIM-19 mediates cellular responses to retinoic acid (in combination with IFN-beta) in the apoptotic pathway. Genuine moonlighting function; non-core. Keep as non-core. Supporting Evidence: PMID:17297443 IFN/all-trans retinoic acid (RA)-dependent manner |
| GO:0045039 protein insertion into mitochondrial inner membrane | IDA PMID:23271731 The import of the transcription factor STAT3 into mitochondr... | KEEP AS NON CORE | Summary: GRIM-19 acts as a chaperone that recruits STAT3 into mitochondria and enhances its integration into Complex I in the inner membrane. This underpins the annotation, but the term is broader than the specific STAT3-chaperone role (GRIM-19 is not a general inner-membrane insertase). A genuine, non-core moonlighting activity tied to the STAT3 axis. Supporting Evidence: PMID:23271731 acts as a chaperone to recruit STAT3 into mitochondria |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-163217 | ACCEPT | Summary: Reactome (TAS) inner-membrane localization. Correct and core. Accept. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799178 | ACCEPT | Summary: Reactome (TAS) inner-membrane localization. Correct and core. Accept. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799179 | ACCEPT | Summary: Reactome (TAS) inner-membrane localization. Correct and core. Accept. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799191 | ACCEPT | Summary: Reactome (TAS) inner-membrane localization. Correct and core. Accept. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799196 | ACCEPT | Summary: Reactome (TAS) inner-membrane localization. Correct and core. Accept. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799197 | ACCEPT | Summary: Reactome (TAS) inner-membrane localization. Correct and core. Accept. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6799202 | ACCEPT | Summary: Reactome (TAS) inner-membrane localization. Correct and core. Accept. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9839073 | ACCEPT | Summary: Reactome (TAS) inner-membrane localization. Correct and core. Accept. |
| GO:0005739 mitochondrion | IDA PMID:16826196 Coupling mitochondrial respiratory chain to cell death: an e... | ACCEPT | Summary: Direct mitochondrial localization from the study establishing an essential role of Complex I (GRIM-19/NDUFS3) in IFN-beta/RA-induced cancer-cell death. Core mitochondrial localization. Accept. |
| GO:0031966 mitochondrial membrane | IDA PMID:17209039 Identification of mitochondrial complex I assembly intermedi... | ACCEPT | Summary: Direct mitochondrial-membrane localization, coarser parent of the more specific inner-membrane annotations. Correct and core. Accept. |
| GO:0005515 protein binding | IPI PMID:12867595 The cell death regulator GRIM-19 is an inhibitor of signal t... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" (IPI) from the STAT3 interaction. This is arguably the most functionally important GRIM-19 interaction (specific STAT3 binding, driving transcriptional repression), but GO:0005515 itself is uninformative as a molecular function. Retained per policy but marked over-annotated; the biology is captured by the STAT3 transcription-repression annotation and by the core function synthesis. Supporting Evidence: PMID:12867595 the transcription factor STAT3 (signal transducer and activator of |
| GO:0005524 ATP binding | NAS PMID:10924506 Identification of GRIM-19, a novel cell death-regulatory gen... | MARK AS OVER ANNOTATED | Summary: "ATP binding" asserted non-experimentally (NAS) from the discovery paper, which does not demonstrate nucleotide binding. NDUFA13 is a non-catalytic accessory subunit with no recognized nucleotide-binding motif, and UniProt does not list ATP binding among its functions. This is an over-annotation. |
| GO:0005654 nucleoplasm | IDA PMID:10924506 Identification of GRIM-19, a novel cell death-regulatory gen... | KEEP AS NON CORE | Summary: Direct nucleoplasm localization from the discovery paper, which found GRIM-19 to be primarily nuclear. Genuine but tied to the moonlighting (STAT3/cell-death) pool rather than the core mitochondrial function. Keep as non-core. Supporting Evidence: PMID:10924506 GRIM-19 is primarily a nuclear protein |
| GO:0005737 cytoplasm | IDA PMID:10924506 Identification of GRIM-19, a novel cell death-regulatory gen... | KEEP AS NON CORE | Summary: Direct cytoplasmic localization from the discovery paper. Coarse; a cytoplasmic pool is consistent with the nuclear/cytoplasmic distribution of the moonlighting GRIM-19 protein. Genuine but non-core relative to the mitochondrial structural role. Keep as non-core. |
| GO:0005739 mitochondrion | IDA PMID:12611891 The subunit composition of the human NADH dehydrogenase obta... | ACCEPT | Summary: Direct mitochondrial localization from the study identifying GRIM-19 in immunopurified human Complex I. Core mitochondrial localization. Accept. Supporting Evidence: PMID:12611891 These polypeptides include the GRIM-19 protein |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:12867595 The cell death regulator GRIM-19 is an inhibitor of signal t... | MODIFY | Summary: GRIM-19 is a specific inhibitor of STAT3-dependent transcription (it binds the STAT3 transactivation domain and represses target-gene expression without blocking STAT3 phosphorylation or DNA binding). This is a genuine, well-supported moonlighting function. The generic "negative regulation of DNA-templated transcription" is less precise than the STAT-specific process; a more informative term is GO:1904893 (negative regulation of receptor signaling pathway via STAT). Proposed replacements: negative regulation of receptor signaling pathway via STAT Supporting Evidence: PMID:12867595 GRIM-19 inhibits transcription driven by activation of STAT3, but not STAT1 |
| GO:0098803 respiratory chain complex | IDA PMID:12611891 The subunit composition of the human NADH dehydrogenase obta... | MARK AS OVER ANNOTATED | Summary: Membership in a respiratory chain complex, the parent class of the more specific respiratory chain complex I annotation. Correct but redundant/general; the specific GO:0045271 (respiratory chain complex I) annotation is preferred. Supporting Evidence: PMID:12611891 These polypeptides include the GRIM-19 protein |
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Download this section (compressed HTML)Q: Is the STAT3-repressive activity of GRIM-19 exerted by a genuinely nuclear/cytoplasmic pool of the protein, or is it an indirect consequence of GRIM-19 sequestering STAT3 at mitochondria and blocking its nuclear translocation?
Q: Does the mitochondrial STAT3-chaperone activity of GRIM-19 require an assembled Complex I, or can free GRIM-19 recruit STAT3 into the inner membrane independently of holoenzyme assembly?
Q: What is the functional consequence of HTRA2 cleaving NDUFA13 at six sites - does it inactivate Complex I, release a signalling fragment, or is it a bystander event?
Q: Are the interferon-beta/retinoic-acid cell-death phenotypes attributed to GRIM-19 separable from its structural role, or do they simply reflect loss of Complex I and the resulting ROS changes?
Experiment: In an NDUFA13 knockout background, reconstitute with variants that retain Complex I assembly but lose STAT3 binding (guided by the mapped STAT3 transactivation-domain interface) and, conversely, with variants that bind STAT3 but fail to assemble into Complex I. Score Complex I assembly by blue native PAGE, respiration by respirometry, and STAT3 target-gene transcription by RT-qPCR/reporter assay to test whether the two functions dissociate.
Hypothesis: The moonlighting STAT3-regulatory function of NDUFA13 is separable from its structural Complex I role.
Type: separation-of-function mutagenesis with respirometry and reporter assays
Experiment: Express cleavage-resistant NDUFA13 (mutating the six mapped HTRA2 sites) in NDUFA13 knockout cells and measure Complex I holoenzyme and supercomplex levels, oxygen consumption, XIAP turnover and apoptotic sensitivity to IFN-beta/retinoic acid, compared with wild-type reconstitution.
Hypothesis: HTRA2-mediated cleavage of NDUFA13 destabilises Complex I and contributes to apoptotic commitment.
Type: cleavage-site mutagenesis with apoptosis and complexome readouts
Experiment: Knock the R57H variant into an isogenic cell line and determine the resulting Complex I structure by cryo-EM alongside quantitative complexome profiling and metabolic-flux measurement, to localise the destabilised interface and relate residual holoenzyme levels to residual NADH:ubiquinone oxidoreductase activity.
Hypothesis: The patient R57H NDUFA13 variant causes disease by destabilising the interface between NDUFA13 and the Complex I matrix arm.
Type: cryo-EM and complexome profiling of a knock-in disease variant
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