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NDUFV1

NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial · UniProt P49821

Length
464 aa
Mass
50.8 kDa
Annotated
2026-06-10
36 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NDUFV1 is the flavin (FMN)-binding, NADH-oxidizing core subunit of mitochondrial respiratory complex I (NADH:ubiquinone oxidoreductase), serving as the principal site of NADH binding, electron entry into the respiratory chain, and reactive oxygen species production (PMID:8288251, PMID:26345448). Its coding sequence carries the NADH-, FMN-, and iron-sulfur-binding motifs that underlie this catalytic role (PMID:9571201), and functional dissection of clinical variants in a Yarrowia lipolytica model confirmed that loss of NDUFV1 abolishes complex I-mediated NADH oxidation, with distinct mutations causing failed assembly, loss of flavin cofactor, or reduced catalytic activity (PMID:26345448). Pathogenic substitutions cluster at subunit interfaces and disrupt complex I assembly, and biallelic loss-of-function mutations cause complex I deficiency that is rescued by wild-type cDNA, establishing NDUFV1 as required for both assembly and activity (PMID:36462614, PMID:33182419). Beyond catalysis, NDUFV1 is regulated at multiple levels: its transcription is activated by Sp1 (PMID:17786189), its protein stability is maintained by CYTL1, which competitively blocks MDM2-mediated proteasomal degradation (PMID:35115484), and its mitochondrial import is gated by SBK2-mediated phosphorylation at Ser251, which promotes HSPA1A chaperoning and TOM70-dependent import to sustain complex I activity, respiratory supercomplex assembly, and redox homeostasis (PMID:42153297). NDUFV1 is necessary for mitochondrial homeostasis under oxidative stress (PMID:37029501), and stabilized NDUFV1 additionally interacts with Src kinase to attenuate LDHA tyrosine phosphorylation and suppress glycolytic reprogramming (PMID:35115484). Biallelic and homozygous NDUFV1 mutations cause mitochondrial complex I deficiency in patients (PMID:21696386, PMID:33182419).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1993 Medium

    Establishing the molecular identity of NDUFV1 was the prerequisite for any mechanistic study; the gene was cloned and mapped, and assigned as the 51-kDa flavoprotein subunit and the principal NADH electron-entry site of complex I.

    Evidence PCR cloning and chromosomal localization by FISH and somatic cell hybrid mapping

    PMID:8288251

    Open questions at the time
    • Functional assignment rested on homology rather than direct enzymatic assay
    • No structural model of cofactor binding
  2. 1998 Medium

    Sequence analysis answered which cofactors NDUFV1 binds and how it is expressed, identifying NADH-, FMN-, and Fe-S-binding motifs and a CpG-island, TATA-less promoter consistent with housekeeping regulation.

    Evidence cDNA/genomic cloning, sequence motif analysis, and Northern blotting

    PMID:9571201

    Open questions at the time
    • Cofactor-binding motifs not functionally verified
    • Promoter elements identified but transcriptional regulators not yet defined
  3. 2007 Medium

    The identity of an upstream transcriptional regulator was addressed by showing Sp1 directly activates NDUFV1 transcription, linking complex I subunit expression to a defined transcription factor.

    Evidence Mithramycin inhibition, promoter-reporter assays, and Sp1 DNA-binding assays in neuroblastoma cells

    PMID:17786189

    Open questions at the time
    • Much of the direct promoter-binding evidence came from the related NDUFV2 promoter
    • Conditions controlling Sp1-driven NDUFV1 expression in vivo unknown
  4. 2011 Low

    A patient mutation linked a specific residue to Fe-S cluster coordination, indicating Arg386 is critical for cluster binding and connecting NDUFV1 genotype to complex I deficiency.

    Evidence Homozygosity mapping, Sanger sequencing, and structural conservation analysis in consanguineous siblings

    PMID:21696386

    Open questions at the time
    • No direct biochemical reconstitution of Fe-S coordination
    • Single family observation
    • Causality inferred from conservation rather than functional assay
  5. 2015 High

    A systematic variant-effect study resolved how clinical NDUFV1 substitutions damage the enzyme, distinguishing assembly loss, flavin-cofactor loss, and catalytic impairment, and confirmed NDUFV1 as the FMN-binding, ROS-producing subunit.

    Evidence Site-directed mutagenesis with yeast complementation, in vitro enzyme assays, and flavin quantification in Yarrowia lipolytica

    PMID:26345448

    Open questions at the time
    • Performed in a yeast model rather than human complex I
    • Three variants showed wild-type behavior, leaving their pathogenicity unresolved
  6. 2020 Medium

    Complementation in patient cells provided direct causal proof that NDUFV1 is required for complex I assembly and activity, since restoring wild-type cDNA rescued the deficiency.

    Evidence Complementation in patient-derived cells with BN-PAGE assembly analysis, spectrophotometric activity assay, and Western blotting

    PMID:33182419

    Open questions at the time
    • Single patient genetic background
    • Did not resolve which assembly intermediate fails
  7. 2022 Medium

    Two studies extended NDUFV1 biology beyond catalysis: one showed pathogenic mutations disrupt assembly at subunit interfaces, the other revealed post-translational stabilization by CYTL1 and a moonlighting role suppressing glycolysis via Src/LDHA.

    Evidence Bacterial nuoF mutagenesis with assembly assays; and Co-IP, MDM2 ubiquitination, Src interaction and LDHA phosphorylation assays in breast cancer cells

    PMID:35115484 PMID:36462614

    Open questions at the time
    • Assembly interface effects modeled in E. coli homolog, not human complex I
    • CYTL1/Src/LDHA axis from a single unreplicated lab
    • Relationship between mitochondrial and putative cytosolic NDUFV1 pools unclear
  8. 2023 Medium

    An in vivo stress model established that NDUFV1 levels are limiting for mitochondrial homeostasis, with overexpression protecting and knockdown aggravating oxidative injury.

    Evidence Mouse renal ischemia-reperfusion overexpression and siRNA knockdown in renal tubular cells with complex I activity, morphology, oxidative stress, and apoptosis readouts

    PMID:37029501

    Open questions at the time
    • Mechanism by which NDUFV1 levels limit homeostasis not dissected
    • Confined to renal stress context
  9. 2026 High

    The pathway controlling NDUFV1 mitochondrial import was defined, showing SBK2 phosphorylates Ser251 to promote HSPA1A chaperoning and TOM70-dependent import, coupling a kinase signal to complex I assembly, supercomplex formation, and OXPHOS.

    Evidence In vitro kinase assay, Co-IP, interactome analysis, fractionation, BN-PAGE, and S251A phospho-deficient rescue in cardiomyocytes

    PMID:42153297

    Open questions at the time
    • Upstream signals regulating SBK2 activity unknown
    • Demonstrated mainly in cardiomyocyte/hypertrophy context

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the distinct regulatory layers — Sp1-driven transcription, CYTL1/MDM2-controlled stability, and SBK2/HSPA1A/TOM70-gated import — are integrated, and whether a non-mitochondrial NDUFV1 pool genuinely modulates glycolysis under physiological conditions.
  • No structural model of human NDUFV1 cofactor sites
  • Cross-talk between regulatory mechanisms untested
  • Cytosolic vs mitochondrial functional partitioning undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 2 GO:0140098 catalytic activity, acting on RNA 2
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-1430728 Metabolism 3
Partners
CYTL1HSPA1AMDM2SBK2SP1SRCTOM70
Complex memberships
mitochondrial respiratory complex Irespiratory supercomplex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 NDUFV1 encodes the 51-kDa flavoprotein subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase) and is the principal site of NADH binding and electron entry into the respiratory chain; the gene was chromosomally localized to 11q13 using PCR-generated cDNA fragments and two independent mapping techniques. PCR cloning, chromosomal localization (fluorescence in situ hybridization and somatic cell hybrid mapping) Genomics Medium 8288251
1998 The NDUFV1 gene contains consensus motifs for NADH, FMN, and iron-sulfur (Fe-S) binding within its coding sequence, consistent with its role as the flavin-binding, NADH-oxidizing subunit of complex I. The 5′ flanking region contains a putative NRF-2 binding site, a GATA-box, and a GC-box but no TATA or CCAAT boxes; the transcriptional start site lies within a CpG island consistent with housekeeping expression. cDNA and genomic cloning, sequence analysis, Northern blotting Biochemical and biophysical research communications Medium 9571201
2007 The transcription factor Sp1 directly activates NDUFV1 transcription; pharmacological inhibition of Sp1-DNA binding with mithramycin reduced NDUFV1 mRNA in neuroblastoma cells, and Sp1 bound and activated the NDUFV2 promoter through three GC-boxes (a closely related finding establishing the Sp1-complex I subunit regulatory axis). mithramycin inhibitor treatment, promoter-reporter assays, Sp1 DNA-binding assays in neuroblastoma cells PloS one Medium 17786189
2015 Using a Yarrowia lipolytica yeast model, 16 clinically identified NDUFV1 single amino-acid substitutions were functionally characterized: 7 caused loss of complex I expression; 2 variants yielded fully assembled complex I lacking flavin cofactor (FMN); 4 produced functionally compromised enzymes with reduced activity; and 3 variants produced complex I functionally equivalent to wild-type, challenging their pathogenic classification. NDUFV1 was confirmed as the flavin (FMN)-binding subunit whose loss abolishes complex I-mediated NADH oxidation and is the site of reactive oxygen species production. Site-directed mutagenesis, yeast complementation, in vitro enzyme activity assays, flavin quantification, structural and bioinformatic analysis Human molecular genetics High 26345448
2022 CYTL1 directly binds the N-terminal sequence of NDUFV1 and competitively blocks MDM2-mediated proteasomal degradation of NDUFV1, thereby stabilizing the NDUFV1 protein. Stabilized NDUFV1 in turn interacts with Src kinase to attenuate LDHA phosphorylation at tyrosine 10, reducing lactate production and suppressing glycolytic reprogramming in breast cancer cells. Co-immunoprecipitation, pulldown assays, MDM2 ubiquitination assay, Src kinase interaction assay, LDHA phosphorylation assay, loss-of-function and gain-of-function cellular studies Signal transduction and targeted therapy Medium 35115484
2022 Multiple pathogenic NDUFV1 mutations (in NDUFS1, NDUFS2, NDUFS8, and NDUFV1 subunits modeled in the E. coli homolog NuoF) map to subunit interfaces and disrupt complex I assembly rather than solely catalytic activity; compound heterozygous combinations were dissected to identify which allele is more deleterious. Assembly defects were demonstrated by co-immunoprecipitation and time-delayed expression assays. Bacterial mutagenesis of E. coli nuoF (NDUFV1 homolog), deamino-NADH oxidase activity assays, co-immunoprecipitation, time-delayed expression assays Mitochondrion Medium 36462614
2023 Overexpression of NDUFV1 in renal ischemia-reperfusion injury mice improved mitochondrial integrity and complex I assembly and activity, reduced oxidative stress and apoptosis, and attenuated kidney dysfunction; conversely, Ndufv1 knockdown in TCMK-1 cells aggravated H2O2-induced cell injury, establishing NDUFV1 as necessary for maintaining mitochondrial homeostasis under oxidative stress. In vivo overexpression (mouse model), siRNA knockdown in renal tubular cells, complex I activity assay, mitochondrial morphology assessment, oxidative stress and apoptosis assays Journal of cellular and molecular medicine Medium 37029501
2026 SBK2 kinase directly binds and phosphorylates NDUFV1 at serine 251. This phosphorylation enhances the interaction of NDUFV1 with the cytosolic chaperone HSPA1A and facilitates TOM70-dependent mitochondrial import of NDUFV1. Increased mitochondrial NDUFV1 promotes complex I activity, respiratory supercomplex assembly, oxidative phosphorylation, mitochondrial fusion, and redox homeostasis; a phospho-deficient S251A NDUFV1 mutant failed to rescue hypertrophic phenotypes in SBK2-deficient cardiomyocytes. In vitro kinase assay, co-immunoprecipitation, proteomic/interactome analysis, biochemical fractionation, blue native PAGE, cardiomyocyte loss- and gain-of-function, phospho-deficient mutant rescue experiment Circulation research High 42153297
2011 The NDUFV1 residue Arg386 is essential for coordinating an iron-sulfur cluster; the p.Arg386His mutation, identified by homozygosity mapping in consanguineous siblings with complex I deficiency, affects a highly conserved residue contiguous to a cysteine known to coordinate an Fe ion, validating the current molecular model of Fe-S clusters in NDUFV1. Homozygosity mapping, Sanger sequencing, structural conservation analysis Clinical genetics Low 21696386
2020 Biallelic loss-of-function mutations in NDUFV1 result in loss of NDUFV1 protein, defective complex I assembly, and reduced complex I enzyme activity; complementation with wild-type NDUFV1 cDNA restored NDUFV1 protein levels, complex I assembly, and enzyme activity, demonstrating that NDUFV1 is required for complex I assembly and function. Complementation assay in patient-derived cells, complex I assembly analysis (BN-PAGE), spectrophotometric enzyme activity assay, Western blotting Genes Medium 33182419

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency. American journal of human genetics 218 11349233
2007 Sp1 expression is disrupted in schizophrenia; a possible mechanism for the abnormal expression of mitochondrial complex I genes, NDUFV1 and NDUFV2. PloS one 69 17786189
2012 Leigh syndrome associated with mitochondrial complex I deficiency due to novel mutations In NDUFV1 and NDUFS2. Gene 49 23266820
2007 Early-onset ophthalmoplegia in Leigh-like syndrome due to NDUFV1 mutations. Pediatric neurology 48 17162199
2015 Characterization of clinically identified mutations in NDUFV1, the flavin-binding subunit of respiratory complex I, using a yeast model system. Human molecular genetics 44 26345448
2015 Broad phenotypic variability in patients with complex I deficiency due to mutations in NDUFS1 and NDUFV1. Mitochondrion 31 25615419
1993 Chromosomal localization of the human gene encoding the 51-kDa subunit of mitochondrial complex I (NDUFV1) to 11q13. Genomics 31 8288251
2008 MR spectroscopy and serial magnetic resonance imaging in a patient with mitochondrial cystic leukoencephalopathy due to complex I deficiency and NDUFV1 mutations and mild clinical course. Neuropediatrics 30 18991197
2022 Intracellular CYTL1, a novel tumor suppressor, stabilizes NDUFV1 to inhibit metabolic reprogramming in breast cancer. Signal transduction and targeted therapy 25 35115484
2011 A novel NDUFV1 gene mutation in complex I deficiency in consanguineous siblings with brainstem lesions and Leigh syndrome. Clinical genetics 25 21696386
1998 Cloning of the human mitochondrial 51 kDa subunit (NDUFV1) reveals a 100% antisense homology of its 3'UTR with the 5'UTR of the gamma-interferon inducible protein (IP-30) precursor: is this a link between mitochondrial myopathy and inflammation? Biochemical and biophysical research communications 21 9571201
2023 NDUFV1 attenuates renal ischemia-reperfusion injury by improving mitochondrial homeostasis. Journal of cellular and molecular medicine 18 37029501
2013 A novel familial case of diffuse leukodystrophy related to NDUFV1 compound heterozygous mutations. Mitochondrion 18 23562761
2018 Late-Onset Leigh Syndrome due to NDUFV1 Mutation in a 10-Year-Old Boy Initially Presenting with Ataxia. Journal of pediatric neurosciences 17 30090137
2018 Cystic Leucoencephalopathy in NDUFV1 Mutation. Indian journal of pediatrics 15 29948731
2021 NDUFV1 mutations in complex I deficiency: Case reports and review of symptoms. Genetics and molecular biology 14 34807224
2020 Leigh Syndrome Due to NDUFV1 Mutations Initially Presenting as LBSL. Genes 13 33182419
2018 A Heterozygous NDUFV1 Variant Aggravates Mitochondrial Complex I Deficiency in a Family with a Homoplasmic ND1 Variant. The Journal of pediatrics 13 29395179
2020 Induced pluripotent stem cell line UOMi002-A from a patient with Leigh syndrome with compound heterozygous mutations in the NDUFV1 gene. Stem cell research 12 32871395
2022 Compound heterozygous mutations of NDUFV1 identified in a child with mitochondrial complex I deficiency. Genes & genomics 9 35482246
2022 The neuropathologic findings in a case of progressive cavitating leukoencephalopathy due to NDUFV1 pathogenic variants. Acta neuropathologica communications 9 36163075
2023 A cryptic pathogenic NDUFV1 variant identified by RNA-seq in a patient with normal complex I activity in muscle and transient magnetic resonance imaging changes. American journal of medical genetics. Part A 7 36896486
2024 NDUFV1-Related Mitochondrial Complex-1 Disorders: A Retrospective Case Series and Literature Review. Pediatric neurology 6 38626668
1999 The structure of the human NDUFV1 gene encoding the 51-kDa subunit of mitochondrial complex I. Mammalian genome : official journal of the International Mammalian Genome Society 6 9892733
2022 Overexpression of NDUFV1 alleviates renal damage by improving mitochondrial function in unilateral ureteral obstruction model mice. Cell biology international 4 34936716
2022 Early-onset leukoencephalomyelopathy due to a biallelic NDUFV1 variant in a mid-forties patient. Annals of clinical and translational neurology 4 35482023
2022 Analysis of compound heterozygous and homozygous mutations found in peripheral subunits of human respiratory Complex I, NDUFS1, NDUFS2, NDUFS8 and NDUFV1, by modeling in the E. coli enzyme. Mitochondrion 4 36462614
2025 Mitochondrial complex I deficiency in a 4-year-old boy due to compound heterozygous NDUFV1 mutation: a case report of a new pathogenic variant. Oxford medical case reports 1 40207266
2024 Leigh Syndrome Caused by Compound Heterozygous Variants c.1162A_C and c.1138G_C in the NDUFV1 Gene: A Case Report. Cureus 1 39525154
2026 Novel NDUFV1 variant in progressive cavitating leukodystrophy with microcephaly: a case report. BMC pediatrics 0 41952138
2026 SBK2-Driven NDUFV1 Phosphorylation and Translocation Limits Cardiac Hypertrophy. Circulation research 0 42153297
2025 NDUFV1 mutation presenting as isolated progressive optic neuropathy: a unique manifestation of mitochondrial complex I deficiency. BMJ case reports 0 40681182
2025 Acute profound lactic alkalosis associated with NDUFV1 compound heterozygosity in a previously healthy 6-year-old female. Molecular genetics and metabolism reports 0 40919011
2025 Progressive spinal cord involvement in Leigh syndrome due to an NDUFV1 variant. Radiology case reports 0 41140551
2022 Expression Study of NDUFS1, NDUFV1, and NDUFV2 in Schizophrenia and Paranoid Personality Disorder : Role of Mitochondrial Complex I in SCZ and PPD. Galen medical journal 0 42040813
2021 [A novel frameshift NDUFV1 mutation in a child with the phenotype of optic nerve atrophy]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 0 34134969

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