Affinage

NDUFV1

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

Length
464 aa
Mass
50.8 kDa
Annotated
2026-04-29
35 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NDUFV1 encodes the 51-kDa flavoprotein subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase), serving as the primary NADH oxidation site and electron entry point into the respiratory chain. The subunit binds the FMN cofactor required for NADH oxidation and coordinates iron–sulfur clusters essential for electron transfer; pathogenic missense mutations either abolish FMN binding, disrupt Complex I assembly at subunit interfaces, or impair catalytic activity, and complementation with wild-type NDUFV1 rescues protein level, assembly, and enzymatic function (PMID:26345448, PMID:33182419, PMID:36462614). Beyond its canonical respiratory chain role, NDUFV1 protein stability is regulated by CYTL1-mediated competitive blockade of MDM2-dependent proteasomal degradation; stabilized NDUFV1 interacts with Src kinase to suppress LDHA-Y10 phosphorylation, thereby restraining aerobic glycolysis (PMID:35115484). Biallelic loss-of-function mutations in NDUFV1 cause mitochondrial Complex I deficiency presenting as Leigh syndrome and leukoencephalopathy (PMID:33182419, PMID:21696386).

Mechanistic history

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

    Identification of NDUFV1 as the gene encoding the 51-kDa flavoprotein of Complex I established the molecular identity of the principal NADH oxidation site and electron entry point of the mitochondrial respiratory chain.

    Evidence PCR-based chromosomal localization, FISH, and sequence motif analysis revealing NADH, FMN, and Fe-S binding sites

    PMID:8288251

    Open questions at the time
    • No direct enzymatic reconstitution performed at this stage
    • Functional consequence of individual binding motifs not tested by mutagenesis
  2. 1998 Medium

    Characterization of the 10-exon genomic structure, CpG island promoter, and NRF-2 binding site established NDUFV1 as a housekeeping gene under transcriptional control relevant to mitochondrial biogenesis.

    Evidence Genomic cloning, cDNA sequencing, Northern blotting, and promoter motif analysis

    PMID:9571201

    Open questions at the time
    • NRF-2-dependent transcriptional regulation not tested functionally
    • Biological significance of the antisense homology to IP-30 3′UTR unknown
  3. 2007 Medium

    Demonstration that Sp1 directly activates NDUFV1 transcription identified a specific transcription factor pathway controlling expression of this core respiratory chain subunit.

    Evidence Mithramycin-mediated Sp1 inhibition with mRNA quantification in neuroblastoma cells

    PMID:17786189

    Open questions at the time
    • Direct Sp1 binding to the NDUFV1 promoter not confirmed by ChIP
    • Relative contributions of Sp1 versus NRF-2 to physiological NDUFV1 expression unresolved
  4. 2011 Medium

    The p.Arg386His mutation established that Arg386 is critical for iron–sulfur cluster coordination in the 4Fe-4S domain of NDUFV1, linking structural integrity of the Fe-S center to disease pathogenesis.

    Evidence Homozygosity mapping, Sanger sequencing, conservation analysis, and structural modeling in patients with Complex I deficiency

    PMID:21696386

    Open questions at the time
    • No direct biochemical measurement of Fe-S cluster content or redox activity for this mutant
    • Functional impact inferred from structural proximity rather than reconstituted enzyme assays
  5. 2015 High

    Systematic mutagenesis of 16 pathogenic NDUFV1 variants resolved how individual mutations cause disease—either by preventing FMN incorporation, abolishing Complex I assembly, or producing catalytically impaired enzyme—and reclassified three variants as non-pathogenic.

    Evidence Yarrowia lipolytica reconstitution with assembly assays, flavin content measurement, and NADH oxidation activity for each variant

    PMID:26345448

    Open questions at the time
    • ROS production rates of individual mutant enzymes not quantified
    • Findings in yeast model await confirmation in mammalian Complex I context
  6. 2020 High

    Complementation rescue in patient-derived cells provided direct proof that NDUFV1 is required for Complex I assembly and enzymatic activity, closing the gap between genetic association and biochemical causality.

    Evidence Patient-derived cell lines with biallelic mutations; Western blot, BN-PAGE, spectrophotometric Complex I assay, and rescue by wild-type NDUFV1 re-expression

    PMID:33182419

    Open questions at the time
    • Tissue-specific consequences (e.g., in neurons) not modeled
    • Supercomplex formation status in rescued cells not assessed
  7. 2022 High

    Discovery that CYTL1 stabilizes NDUFV1 by blocking MDM2-mediated proteasomal degradation, and that stabilized NDUFV1 interacts with Src to suppress LDHA-Y10 phosphorylation, revealed an unexpected non-respiratory function of NDUFV1 in restraining glycolytic reprogramming.

    Evidence Reciprocal Co-IP, proteasome inhibitor experiments, metabolic assays, and in vivo tumor models in breast cancer cells

    PMID:35115484

    Open questions at the time
    • Whether the NDUFV1-Src interaction occurs in non-cancer tissues is unknown
    • Structural basis for competitive binding between CYTL1 and MDM2 on NDUFV1 N-terminus not resolved
    • Whether the glycolytic regulatory role requires NDUFV1's enzymatic activity or is purely scaffolding is unclear
  8. 2022 Medium

    Modeling compound heterozygous NDUFV1 variants at subunit interfaces in the bacterial homolog nuoF demonstrated that interface mutations reduce both NADH oxidase activity and complex assembly, establishing subunit contacts as critical for enzyme integrity.

    Evidence E. coli mutagenesis with membrane vesicle NADH oxidase assays, Co-IP, and time-delayed expression assays

    PMID:36462614

    Open questions at the time
    • Bacterial system lacks eukaryotic assembly factors and supercomplexes
    • Quantitative correlation between assembly defect severity and patient phenotype not established
  9. 2023 Medium

    Gain- and loss-of-function experiments in renal ischemia-reperfusion injury demonstrated that NDUFV1 levels are rate-limiting for maintaining mitochondrial integrity, Complex I function, and cell survival under oxidative stress.

    Evidence In vivo mouse renal I/R model with NDUFV1 overexpression; siRNA knockdown in TCMK-1 cells with Complex I activity, mitochondrial morphology, and apoptosis assays

    PMID:37029501

    Open questions at the time
    • Whether NDUFV1 overexpression benefits are mediated solely through Complex I activity or also through non-respiratory interactions (e.g., Src/LDHA axis) is unexplored
    • Long-term renal outcomes not assessed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for how NDUFV1 integrates into mammalian supercomplexes, whether its Src-dependent glycolytic regulatory function operates in normal physiology beyond cancer, and the quantitative relationship between residual NDUFV1 activity and clinical severity across different tissue types.
  • No high-resolution structure of human NDUFV1 in the context of supercomplex assembly intermediates
  • Non-respiratory functions of NDUFV1 tested only in cancer cell lines
  • Genotype-phenotype correlations across tissues not systematically established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0098772 molecular function regulator activity 1
Localization
GO:0005739 mitochondrion 4
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-1643685 Disease 2
Partners
CYTL1LDHAMDM2SRC
Complex memberships
Complex I (NADH:ubiquinone oxidoreductase)

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 NDUFV1 encodes the 51-kDa flavoprotein subunit of mitochondrial NADH:ubiquinone oxidoreductase (Complex I), playing an important role in formation of the NADH-binding site and serving as the principal site of electron entry from NADH into the respiratory chain. The gene was chromosomally localized to 11q13. PCR-based chromosomal localization (fluorescence in situ hybridization and somatic cell hybrid analysis); sequence analysis revealing NADH, FMN, and iron-sulfur binding site motifs Genomics High 8288251
1998 The NDUFV1 gene contains consensus motifs for NADH, FMN, and iron-sulfur binding within its coding sequence. Its 10-exon genomic structure was characterized, with a CpG island at the transcriptional start site (consistent with housekeeping function) and an NRF-2 binding site in the 5' flanking region. An unexpected 48-bp antisense homology between the NDUFV1 3'UTR and the 5'UTR of gamma-interferon inducible protein (IP-30) was identified. Genomic cloning, cDNA sequencing, Northern blotting, sequence motif analysis Biochemical and biophysical research communications Medium 9571201
2007 Transcription factor Sp1 directly activates NDUFV1 transcription; inhibition of Sp1/DNA binding by mithramycin reduced NDUFV1 mRNA levels in neuroblastoma cells, demonstrating Sp1 as a transcriptional regulator of NDUFV1. Pharmacological inhibition of Sp1 with mithramycin, promoter-binding assays, mRNA quantification in neuroblastoma cells PloS one Medium 17786189
2015 NDUFV1 binds the flavin (FMN) cofactor that oxidizes NADH and is the site of Complex I-mediated reactive oxygen species (ROS) production. Sixteen pathogenic missense mutations were functionally characterized: some caused loss of complex I expression, two resulted in assembled but flavin-free complex I, and four produced functionally compromised enzymes; three variants yielded wild-type-equivalent function, challenging their pathogenic assignment. Yarrowia lipolytica yeast model system; complex I assembly assays, flavin content measurement, NADH oxidation activity assays, mutagenesis of all 16 variants Human molecular genetics High 26345448
2011 Arg386 in NDUFV1 is critical for coordinating iron-sulfur clusters; the p.Arg386His mutation affects a conserved residue contiguous to a cysteine that coordinates an Fe ion in the 4Fe-4S domain, validating the molecular model of iron-sulfur cluster coordination by NDUFV1. Homozygosity mapping, Sanger sequencing, protein conservation analysis, structural modeling Clinical genetics Medium 21696386
2022 CYTL1 protein competitively binds the N-terminal sequence of NDUFV1 to block MDM2-mediated proteasomal degradation of NDUFV1, thereby stabilizing NDUFV1 protein levels. Stabilized NDUFV1 in turn interacts with Src kinase to attenuate LDHA phosphorylation at tyrosine 10, reducing lactate production and inhibiting glycolytic reprogramming in breast cancer cells. Co-immunoprecipitation, pulldown assays, proteasome inhibitor experiments, NDUFV1 overexpression/knockdown, metabolic assays (glucose uptake, lactate production), in vitro and in vivo tumor models Signal transduction and targeted therapy High 35115484
2022 Pathogenic mutations in NDUFV1 mapped to subunit interfaces disrupt Complex I assembly; compound heterozygous variants in NDUFV1 (modeled in the homologous E. coli nuoF subunit) showed reduced NADH oxidase activity and impaired complex assembly as measured by co-immunoprecipitation and time-delayed expression assays. E. coli model system mutagenesis, membrane vesicle NADH oxidase activity assays, co-immunoprecipitation assembly assays, time-delayed expression assays Mitochondrion Medium 36462614
2023 NDUFV1 overexpression in renal tubular cells improves mitochondrial integrity and Complex I activity, reduces oxidative stress and apoptosis following ischemia-reperfusion injury; NDUFV1 knockdown aggravated H2O2-induced cell injury, establishing NDUFV1 as required for maintaining mitochondrial homeostasis and Complex I function. In vivo mouse renal I/R model with NDUFV1 overexpression, siRNA knockdown in TCMK-1 cells, Complex I activity assays, mitochondrial morphology assessment, oxidative stress and apoptosis assays Journal of cellular and molecular medicine Medium 37029501
2020 Biallelic loss-of-function mutations in NDUFV1 cause loss of NDUFV1 protein, defective Complex I assembly, and reduced Complex I enzyme activity; complementation with wild-type NDUFV1 restored NDUFV1 protein level, Complex I assembly, and enzyme activity, directly demonstrating the requirement of NDUFV1 for Complex I assembly and function. Patient-derived cell lines, Western blot for NDUFV1 protein, blue-native PAGE for Complex I assembly, spectrophotometric Complex I enzyme assay, complementation assay with NDUFV1 re-expression Genes High 33182419

Source papers

Stage 0 corpus · 35 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 68 17786189
2012 Leigh syndrome associated with mitochondrial complex I deficiency due to novel mutations In NDUFV1 and NDUFS2. Gene 48 23266820
2007 Early-onset ophthalmoplegia in Leigh-like syndrome due to NDUFV1 mutations. Pediatric neurology 47 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
1993 Chromosomal localization of the human gene encoding the 51-kDa subunit of mitochondrial complex I (NDUFV1) to 11q13. Genomics 31 8288251
2015 Broad phenotypic variability in patients with complex I deficiency due to mutations in NDUFS1 and NDUFV1. Mitochondrion 30 25615419
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
2011 A novel NDUFV1 gene mutation in complex I deficiency in consanguineous siblings with brainstem lesions and Leigh syndrome. Clinical genetics 25 21696386
2022 Intracellular CYTL1, a novel tumor suppressor, stabilizes NDUFV1 to inhibit metabolic reprogramming in breast cancer. Signal transduction and targeted therapy 24 35115484
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
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
2023 NDUFV1 attenuates renal ischemia-reperfusion injury by improving mitochondrial homeostasis. Journal of cellular and molecular medicine 16 37029501
2018 Cystic Leucoencephalopathy in NDUFV1 Mutation. Indian journal of pediatrics 14 29948731
2021 NDUFV1 mutations in complex I deficiency: Case reports and review of symptoms. Genetics and molecular biology 13 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 2 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
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