Affinage

NDUFA11

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 · UniProt Q86Y39

Length
141 aa
Mass
14.9 kDa
Annotated
2026-06-10
41 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NDUFA11 (B14.7) is a nuclear-encoded, four-transmembrane-helix subunit of the membrane arm of mitochondrial respiratory complex I that originates from the Tim17/Tim22/Tim23 family of inner-membrane protein translocases (PMID:12381726, PMID:27760563). It is an integral component of intact complex I (PMID:12644575) and is required for assembly of the complex I membrane arm: its loss causes accumulation of ~550 and ~815 kDa subcomplexes together with a defined set of extrinsic assembly factors (PMID:24191001). Within respirasomes, structural analysis places NDUFA11 at the interface between complex I and complexes III/IV, where it contributes to oligomerization of the CI-CIII-CIV supercomplex (PMID:27912063); consistent with this, NDUFA11 depletion dissociates the respirasome, lowers complex I/III/IV activities, reduces ATP production, and raises mitochondrial ROS (PMID:30531981), and disrupts cristae architecture with widened cristae junctions (PMID:34106255). Loss of NDUFA11 elicits an adaptive long-term translational stress response and drives ROS-dependent Tau dimerization (PMID:31116686, PMID:35446108). NDUFA11 forms a complex with the complex I subunit NDUFS1 whose abundance is reduced in ischemic and seizure pathology, and restoring this complex supports neuronal survival and suppresses disulfidptosis (PMID:41236076, PMID:39805370). A splice-site mutation deleting its first transmembrane domain destabilizes complex I and causes human complex I deficiency presenting as encephalocardiomyopathy or fatal infantile lactic acidemia (PMID:18306244).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2002 High

    Establishing that an uncharacterized hydrophobic protein was a bona fide complex I subunit defined NDUFA11's molecular identity and its surprising evolutionary kinship to inner-membrane protein translocases.

    Evidence Reverse-phase HPLC, 1D/2D gel electrophoresis, peptide mass fingerprinting, and cDNA cloning of bovine heart complex I subcomplex Ialpha

    PMID:12381726

    Open questions at the time
    • Functional consequence of Tim17-family homology not tested
    • Topology of the four predicted transmembrane helices not experimentally mapped
  2. 2003 High

    Confirming NDUFA11 across multiple isolated subcomplexes secured its assignment within the ~980 kDa, 46-subunit intact complex I.

    Evidence SDS-PAGE, 2D IEF/SDS-PAGE, HPLC, and tandem MS of purified bovine complex I subcomplexes Ilambda and Ibeta

    PMID:12644575

    Open questions at the time
    • Did not address assembly role or position within the membrane arm
  3. 2008 Medium

    A human loss-of-function mutation answered whether NDUFA11 is physiologically required, linking its disruption directly to complex I deficiency disease.

    Evidence Homozygosity mapping and mutation analysis of patients with a splice-site mutation removing the first transmembrane domain, plus patient biochemical studies

    PMID:18306244

    Open questions at the time
    • Mechanism inferred from predicted domain loss, not reconstituted
    • Why phenotype ranges from encephalocardiomyopathy to fatal lactic acidemia not resolved
  4. 2013 High

    Knockdown defined NDUFA11's biogenesis role, showing it is needed to build the complex I membrane arm rather than merely decorate the mature enzyme.

    Evidence siRNA knockdown with blue-native PAGE detection of ~550 and ~815 kDa subcomplexes and MS identification of associated assembly factors

    PMID:24191001

    Open questions at the time
    • Order of incorporation relative to assembly factors not established
    • Direct interactions within subcomplexes not mapped
  5. 2016 High

    Structural placement and phylogenetic analysis explained how a translocase-derived subunit functions, positioning NDUFA11 at the supercomplex interface as a diversified Tim17-family member.

    Evidence 4.0 Å cryo-EM of the porcine I1III2IV1 supercomplex; sequence/phylogenetic analysis across 5631 proteomes

    PMID:27760563 PMID:27912063

    Open questions at the time
    • Specific contacts NDUFA11 makes with CIII/CIV not resolved at side-chain level
    • Whether translocase-like activity is retained not tested
  6. 2018 High

    Functional depletion linked NDUFA11 to respirasome integrity, showing its loss collapses the supercomplex and bioenergetic output while raising ROS.

    Evidence siRNA knockdown in cardioblasts and cardiac mitochondria with BN-PAGE, complex I/II/III/IV activity assays, ATP and ROS measurements

    PMID:30531981

    Open questions at the time
    • Whether respirasome loss is cause or consequence of CI destabilization not disentangled
  7. 2021 High

    Cross-species genetics tied NDUFA11 to organismal viability and connected supercomplex loss to ultrastructural cristae defects.

    Evidence CRISPR knockout (L2 larval arrest) and RNAi in C. elegans with BN-PAGE, respiratory assays, and cryo-electron tomography

    PMID:34106255

    Open questions at the time
    • Mechanistic link between supercomplex loss and cristae junction widening not defined
  8. 2022 Medium

    Knockout studies extended NDUFA11 function downstream into stress signaling and proteostasis, placing its mitochondrial role upstream of an adaptive translational program and ROS-driven Tau aggregation.

    Evidence NDUFA11 knockout in HEK293T with phospho-immunoblotting of mTOR/eIF2α-ATF4 components, BiFC Tau dimerization assay, and ROS-scavenger rescue (NAC, MitoQ)

    PMID:31116686 PMID:35446108

    Open questions at the time
    • Signaling phenotypes from a single cell line
    • How chronic CI deficiency rewires the integrated stress response mechanistically not defined
  9. 2025 Medium

    Identification of an NDUFS1-NDUFA11 complex linked NDUFA11 abundance to neuronal disease outcomes and to a disulfidptosis-suppressing function.

    Evidence Co-IP of NDUFS1-NDUFA11, lentiviral Ndufa11 overexpression, patch-clamp, and OGD/R neuron and seizure models with disulfidptosis marker quantification

    PMID:39805370 PMID:41236076

    Open questions at the time
    • Direct vs indirect nature of NDUFS1-NDUFA11 interaction not fully established
    • Seizure-model finding rests on a single low-confidence Co-IP
    • Mechanism linking the complex to disulfidptosis suppression not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NDUFA11 mechanically nucleates membrane-arm assembly and stabilizes the CI-CIII-CIV interface at the molecular level, and whether any ancestral translocase activity is retained, remains unresolved.
  • No reconstituted assembly intermediate with defined NDUFA11 contacts
  • No high-resolution map of NDUFA11-CIII/CIV interface side chains
  • Functional test of Tim17-family translocase activity absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-1643685 Disease 1
Partners
NDUFS1TIMMDC1
Complex memberships
CI-CIII-CIV respirasome supercomplexRespiratory complex I

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 NDUFA11 (B14.7) was identified as a novel nuclear-encoded subunit of bovine heart mitochondrial complex I, located in subcomplex Ialpha. The protein has an acetylated N terminus, no presequence, contains four potential transmembrane helices, and is homologous to Tim17/Tim22/Tim23 protein translocation components of the inner mitochondrial membrane. Reverse-phase HPLC, 1D and 2D gel electrophoresis, tryptic peptide mass fingerprinting, tandem mass spectrometry, cDNA cloning and sequencing The Journal of biological chemistry High 12381726
2003 NDUFA11 (B14.7) was confirmed as a subunit of bovine heart complex I found in subcomplexes Ilambda and Ibeta, establishing that the intact complex I contains 46 subunits with a mass of ~980 kDa. B14.7 was detected specifically in subcomplex Ilambda by SDS-PAGE and in subcomplex Ibeta by HPLC analysis. 1D SDS-PAGE, 2D isoelectric focusing/SDS-PAGE, reverse-phase HPLC, tryptic peptide mass fingerprinting, tandem mass spectrometry, electrospray ionization MS Molecular & cellular proteomics : MCP High 12644575
2013 Suppression of NDUFA11 expression disrupted assembly of complex I, causing accumulation of subcomplexes at ~550 kDa and ~815 kDa, and was associated with eight known extrinsic assembly factors plus the hydrophobic protein C3orf1 in these subcomplexes. This establishes NDUFA11 as required for constructing the membrane arm of complex I. siRNA knockdown, blue-native PAGE to detect subcomplexes, mass spectrometry of associated assembly factors Proceedings of the National Academy of Sciences of the United States of America High 24191001
2008 A splice-site mutation in NDUFA11 causing loss of the first transmembrane domain destabilizes complex I and causes mitochondrial complex I deficiency, manifesting as encephalocardiomyopathy or fatal infantile lactic acidemia in human patients. Homozygosity mapping, mutation analysis, patient biochemical studies Annals of neurology Medium 18306244
2016 Cryo-EM structure of the porcine respiratory supercomplex I1III2IV1 at 4.0 Å showed that NDUFA11 is directly positioned at the interface between complex I and the other complexes, contributing to the oligomerization of CI, CIII, and CIV within the supercomplex. Cryo-electron microscopy at 4.0 Å resolution, structural assignment of individual subunits Cell High 27912063
2018 Knockdown of NDUFA11 in cardioblast cells and cardiac mitochondria caused dissociation of the respirasome (CI-CIII-CIV supercomplex), reduced activities of complexes I, III, and IV, decreased ATP production, and increased mitochondrial ROS production, establishing NDUFA11 as essential for respirasome assembly and stability. siRNA knockdown, blue-native PAGE, enzyme activity assays for complexes I/II/III/IV, ATP production measurement, ROS measurement Scientific reports High 30531981
2021 In C. elegans, knockout of nduf-11 (NDUFA11 homologue) caused larval arrest at L2, while RNAi knockdown destabilized complex I and its supercomplexes, perturbed respiratory function, enhanced complex II activity (compensatory), caused aberrant cristae morphology with widened cristae junctions and expanded intermembrane space as shown by cryo-electron tomography. CRISPR-Cas9 knockout, RNAi knockdown, blue-native PAGE, respiratory function assays, cryo-electron tomography Journal of cell science High 34106255
2019 Knockout of NDUFA11 in HEK293T cells induced long-term mitochondrial stress that decreased eIF2α (Ser51) phosphorylation and ATF4 expression while increasing S6K1 (Thr389) phosphorylation, demonstrating an adaptive long-term translational response distinct from acute mitochondrial stress. NDUFA11 knockout (HEK293T), phospho-immunoblotting for mTOR pathway components (S6K1, 4E-BP1, eIF2α), ATF4 quantification Molecular biology of the cell Medium 31116686
2022 Long-term mitochondrial stress induced by NDUFA11 knockout in HEK293T cells triggered Tau dimerization (first step of aggregation) via increased ROS; treatment with ROS scavengers (NAC or MitoQ) significantly reduced both ROS levels and Tau dimerization, placing NDUFA11-dependent mitochondrial function upstream of oxidative stress-driven Tau aggregation. NDUFA11 knockout (HEK293T), bimolecular fluorescence complementation assay for Tau dimerization, ROS measurement, ROS scavenger treatment (NAC, MitoQ) Molecular biology of the cell Medium 35446108
2025 NDUFA11 forms a complex with NDUFS1, and this NDUFS1-NDUFA11 complex abundance is decreased in ischemic stroke models in vitro and in vivo. Lentivirus-mediated overexpression of Ndufa11 enhanced NDUFS1-NDUFA11 complex formation, improved neuronal survival and action potential amplitude in OGD/R models, and suppressed disulfidptosis markers (xCT, NADP+/NADPH ratio, cystine uptake). Metformin upregulated Ndufa11 and recapitulated these effects. Co-immunoprecipitation (NDUFS1-NDUFA11 complex), lentiviral Ndufa11 overexpression, patch-clamp electrophysiology, OGD/R primary cortical neuron model, disulfidptosis marker quantification Brain research bulletin Medium 41236076
2025 In epilepsy models, the NDUFS1-NDUFA11 protein complex is decreased (fewer formed complexes detected), placing NDUFA11 as a component of this respiratory complex I subunit interaction that is disrupted in seizure pathology. Co-immunoprecipitation of NDUFS1-NDUFA11 complexes in in vitro and in vivo seizure models, validated against bioinformatics-identified interactions Neurobiology of disease Low 39805370
2021 RORα transcription factor represses ROS generation in breast cancer cells by targeting complex I subunits NDUFS6 and NDUFA11, as identified by gene co-expression analysis and chromatin immunoprecipitation (ChIP), placing NDUFA11 as a transcriptional target of RORα that mediates superoxide suppression. Gene co-expression analysis, chromatin immunoprecipitation (ChIP), ROS measurement, macrophage co-culture assay International journal of molecular sciences Low 34639006
2016 Phylogenetic and sequence analysis established that NDUFA11 belongs to the Tim17 protein family and is one of two Tim17-family members (alongside TIMMDC1) that reside in the mitochondrial inner membrane as part of respiratory complex I assembly, representing a functional diversification of ancestral protein translocase components. Comprehensive sequence analysis across 5631 proteomes, phylogenetic analysis Biology direct Medium 27760563

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Analysis of the subunit composition of complex I from bovine heart mitochondria. Molecular & cellular proteomics : MCP 310 12644575
2016 Structure of Mammalian Respiratory Supercomplex I1III2IV1. Cell 309 27912063
2002 Definition of the nuclear encoded protein composition of bovine heart mitochondrial complex I. Identification of two new subunits. The Journal of biological chemistry 137 12381726
2013 Assembly factors for the membrane arm of human complex I. Proceedings of the National Academy of Sciences of the United States of America 116 24191001
2017 Genetic loci associated with heart rate variability and their effects on cardiac disease risk. Nature communications 103 28613276
2008 Mitochondrial complex I deficiency caused by a deleterious NDUFA11 mutation. Annals of neurology 95 18306244
2016 Evolution of the Tim17 protein family. Biology direct 56 27760563
2018 Elucidating the contribution of ETC complexes I and II to the respirasome formation in cardiac mitochondria. Scientific reports 51 30531981
2012 Low-intensity laser irradiation at 660 nm stimulates transcription of genes involved in the electron transport chain. Photomedicine and laser surgery 49 23240874
2011 Proteomic analysis of mitochondria in APOE transgenic mice and in response to an ischemic challenge. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 45 21878944
2018 Evidence of altered depression and dementia-related proteins in the brains of young rats after ovariectomy. Journal of neurochemistry 43 29939407
2019 Cytosolic translational responses differ under conditions of severe short-term and long-term mitochondrial stress. Molecular biology of the cell 41 31116686
2022 Long-term mitochondrial stress induces early steps of Tau aggregation by increasing reactive oxygen species levels and affecting cellular proteostasis. Molecular biology of the cell 30 35446108
2021 Maintenance of complex I and its supercomplexes by NDUF-11 is essential for mitochondrial structure, function and health. Journal of cell science 30 34106255
2021 RORα Suppresses Cancer-Associated Inflammation by Repressing Respiratory Complex I-Dependent ROS Generation. International journal of molecular sciences 26 34639006
2024 Nuclear Genome-Encoded Mitochondrial OXPHOS Complex I Genes in Female Buffalo Show Tissue-Specific Differences. Molecular biotechnology 22 38878239
2023 Transcriptomic and metabolomic insights into the roles of exogenous β-hydroxybutyrate acid for the development of rumen epithelium in young goats. Animal nutrition (Zhongguo xu mu shou yi xue hui) 19 37746660
2017 Mitochondrial-nuclear crosstalk, haplotype and copy number variation distinct in muscle fiber type, mitochondrial respiratory and metabolic enzyme activities. Scientific reports 17 29070892
2012 A molecular link between mitochondrial preprotein transporters and respiratory chain complexes. Plant signaling & behavior 15 23073015
2016 Identification of crucial regulatory relationships between long non-coding RNAs and protein-coding genes in lung squamous cell carcinoma. Molecular and cellular probes 14 26928440
2022 Comparative analysis of long noncoding RNA and mRNA expression provides insights into adaptation to hypoxia in Tibetan sheep. Scientific reports 13 35449433
2021 Identification of Cross-Pathway Connections via Protein-Protein Interactions Linked to Altered States of Metabolic Enzymes in Cervical Cancer. Frontiers in medicine 9 34790674
2025 Identification of key LncRNAs and mRNAs associated with intramuscular fat in pig via WGCNA. BMC genomics 8 40069611
2022 ARSD is responsible for carcinoma and amyloidosis of breast epithelial cells. European journal of cell biology 6 35066432
2022 Mutation burden analysis of six common mental disorders in African Americans by whole genome sequencing. Human molecular genetics 6 35642741
2022 Proteomic analysis of spinal cord tissue in a rat model of cancer-induced bone pain. Frontiers in molecular neuroscience 6 36545122
2008 Subunit analysis of bovine heart complex I by reversed-phase high-performance liquid chromatography, electrospray ionization-tandem mass spectrometry, and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. Analytical biochemistry 6 18721790
2025 Identifying disulfidptosis-related biomarkers in epilepsy based on integrated bioinformatics and experimental analyses. Neurobiology of disease 4 39805370
2023 MicroRNA and mRNA sequencing analyses reveal key hepatic metabolic and signaling pathways responsive to maternal undernutrition in full-term fetal pigs. The Journal of nutritional biochemistry 3 36871838
2025 NDUFA11 may be the disulfidptosis-related biomarker of ischemic stroke based on integrated bioinformatics, clinical samples, and experimental analyses. Frontiers in neuroscience 2 39877656
2025 Multi-omics analysis reveals the molecular mechanism of silibinin rescue the toxic effects of butyl benzyl phthalate on porcine preimplantation embryos. Journal of hazardous materials 1 40554343
2025 Mechanisms of metformin in alleviating neurological deficits in stroke patients: Involving Ndufa11-mediated mitochondrial protection, enhanced neuronal electrophysiology, and inhibition of disulfidptosis. Brain research bulletin 1 41236076
2024 Functional study on candidate regulators mediating the expression of CYP6B7 induced by fenvalerate in a susceptible strain of Helicoverpa armigera. Pesticide biochemistry and physiology 1 38879320
2023 Proteomic Analysis by 4D Label-free MS-PRM Provides Insight into the Role and Regulatory Mechanisms of IL-25 in NK Cells. Protein and peptide letters 1 37702163
2026 Mitochondrial abnormalities in idiopathic inflammatory myopathies. Clinical and experimental rheumatology 0 41738252
2026 Stage-Specific Transcriptomic Analysis Reveals Molecular Basis of Ovarian Sterility in Triploid Turbot (Scophthalmus maximus). Animals : an open access journal from MDPI 0 42121777
2026 Mitochondrial-Inflammatory Axis Dysregulation Triggers Disulfidptosis and the Multifaceted Protective Mechanism of Bisphenol A Following Spinal Cord Injury. Molecular neurobiology 0 42201472
2025 Investigating the role of disulfidoptosis in spinal cord injury and development of a novel diagnostic model. Acta orthopaedica et traumatologica turcica 0 40726387
2025 Proteomic profiling of bone tissue reveals distinct pathways in men and women with osteoporosis. Age and ageing 0 41104785
2025 Integrative network toxicology, transcriptomic, and molecular docking approaches to elucidate the toxicity and mechanisms of bisphenol A in stroke. BMC pharmacology & toxicology 0 41456051
2023 Generation of Mutants from the 57B Region of Drosophila melanogaster. Genes 0 38002990

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