Affinage

MT-ND4

NADH-ubiquinone oxidoreductase chain 4 · UniProt P03905

Length
459 aa
Mass
51.6 kDa
Annotated
2026-04-28
100 papers in source corpus 17 papers cited in narrative 17 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MT-ND4 encodes a core hydrophobic subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase) that is essential for electron transfer from NAD-linked substrates to ubiquinone and for proper Complex I assembly. Conserved transmembrane charged residues (Glu144 and Lys234 in the bacterial homolog NuoM) are required for proton translocation but not for NADH dehydrogenase activity per se, and their disruption increases superoxide production (PMID:17977822); ND4 is also specifically required for membrane attachment of the 24 kDa nuclear-encoded subunit and is incorporated into the distal membrane module of Complex I with assistance from the assembly factor TMEM126A (PMID:15250827, PMID:33879611). The G11778A mutation (Arg340His) causes Leber hereditary optic neuropathy (LHON) by impairing NAD-linked substrate oxidation without abolishing isolated Complex I catalytic activity, elevating reactive oxygen species in neuronal cells, and triggering mitochondria-dependent apoptosis of retinal ganglion cells; allotopic expression of wild-type ND4 rescues Complex I function and prevents RGC loss (PMID:1959619, PMID:12446713, PMID:17197509, PMID:18513491). Nuclear-encoded wild-type ND4, delivered via AAV or electroporation, is imported into mitochondria, incorporated into Complex I, and functionally replaces the endogenous mutant subunit in patient cells and animal models (PMID:19387075, PMID:18771762).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1991 High

    The first biochemical dissection of the LHON 11778/ND4 mutation revealed that ND4 is not required for rotenone-sensitive NADH:ubiquinone activity in isolated membranes but is essential for efficient oxidation of NAD-linked substrates in intact mitochondria, suggesting ND4 organizes dehydrogenase aggregation with Complex I.

    Evidence Enzymatic assays comparing rotenone-sensitive activity and NAD-linked substrate oxidation in mitochondria from LHON patient cells versus controls

    PMID:1959619

    Open questions at the time
    • Mechanism by which ND4 facilitates NAD-linked substrate channeling not resolved
    • No structural data to explain how Arg340His disrupts function without abolishing catalysis
  2. 1997 High

    Analysis of homoplasmic versus heteroplasmic LHON platelets established that the 11778/ND4 mutation alters Complex I inhibitor sensitivity (rotenone resistance) without markedly reducing specific activity, and that wild-type mtDNA functionally complements the defect in heteroplasmic individuals.

    Evidence Complex I activity and rotenone/rolliniastatin-2 sensitivity assays in platelet mitochondrial particles with mtDNA genotyping

    PMID:9191778

    Open questions at the time
    • Structural basis for altered inhibitor binding not determined
    • Threshold of heteroplasmy for functional complementation not precisely defined
  3. 1998 High

    Modeling the human Arg340His mutation in the bacterial ND4 homolog NuoM recapitulated the human biochemical phenotype—reduced NADH-supported respiration in intact cells but not in membranes, with no effect on proton-pump activity—establishing that this residue is critical for electron transfer but dispensable for proton translocation.

    Evidence Site-directed mutagenesis of NuoM Arg368 in Rhodobacter capsulatus with measurement of NADH-supported respiration and proton-pump activity

    PMID:9685604

    Open questions at the time
    • Mechanism by which Arg340/368 specifically affects electron transfer chain organization not determined
    • Bacterial system lacks mitochondrial membrane complexity
  4. 2001 High

    Functional complementation of ND4-null human cells with yeast NDI1 demonstrated that ND4 is absolutely required for Complex I-dependent respiration, as its loss abolishes rotenone-sensitive NADH oxidation.

    Evidence Complementation of C4T (ND4-null) human cells with nuclear-encoded yeast NDI1; NADH dehydrogenase activity, respirometry, and galactose growth assays

    PMID:11479321

    Open questions at the time
    • NDI1 bypasses Complex I rather than restoring it, so specific assembly role of ND4 was not addressed
  5. 2002 High

    Two studies established the pathological consequences of the ND4 11778 mutation in cellular models: it causes mitochondria-dependent apoptosis under metabolic stress and reveals a differentiation-dependent ROS phenotype specifically in neuronal cells, explaining the tissue selectivity of LHON.

    Evidence Cybrid cells in galactose medium with apoptosis assays (cytochrome c release, DNA laddering); neuronal NT2 cybrid differentiation with ROS measurement and rotenone inhibition

    PMID:11854175 PMID:12446713

    Open questions at the time
    • Why retinal ganglion cells are selectively vulnerable among neuronal types not explained
    • Downstream apoptotic signaling pathway not fully characterized
  6. 2004 High

    Subfractionation of ND4-null mitochondria revealed that ND4 is specifically required for membrane attachment of the 24 kDa nuclear-encoded Complex I subunit, demonstrating a structural assembly role beyond catalysis.

    Evidence Mitochondrial membrane fractionation and western blot of nuclear-encoded Complex I subunits in ND4-null, ND5-null, and rho0 human cell lines

    PMID:15250827

    Open questions at the time
    • Whether ND4 directly contacts the 24 kDa subunit or acts indirectly not resolved
    • Full assembly intermediate containing ND4 not characterized
  7. 2007 High

    Systematic mutagenesis of conserved transmembrane residues in bacterial NuoM identified Glu144 and Lys234 as essential for proton translocation and energy-transducing activities of Complex I, while dispensable for NADH dehydrogenase activity, and showed that their mutation increases superoxide production—establishing the proton-pump contribution of the ND4 module.

    Evidence Site-directed mutagenesis of 15 residues in E. coli NuoM; NDH-1 activity, proton translocation, superoxide, and quinone-binding assays

    PMID:17977822

    Open questions at the time
    • Proton pathway through ND4 not structurally resolved at this point
    • Coupling between proton translocation and electron transfer through ND4 module not mechanistically explained
  8. 2007 High

    In vivo allotopic expression of mutant ND4 (R340H) in mouse retinal ganglion cells recapitulated LHON pathology—elevated ROS, disrupted mitochondrial cytoarchitecture, and progressive RGC apoptosis—while wild-type ND4 was non-toxic, providing the first animal model and proof-of-concept that the ND4 mutation is sufficient to cause optic neuropathy.

    Evidence AAV-mediated allotopic delivery to mouse eyes; MRI, immunohistochemistry, electron microscopy, ROS measurement

    PMID:17197509

    Open questions at the time
    • Whether allotopic expression recapitulates endogenous mtDNA-encoded ND4 stoichiometry not confirmed
    • Long-term durability of the animal model not assessed
  9. 2008 High

    Two independent studies demonstrated that nuclear-encoded wild-type ND4 can be imported into mitochondria and functionally replace the mutant subunit: allotopic expression rescued Complex I activity and ATP synthesis in patient fibroblasts, and in vivo electroporation of wild-type ND4 prevented RGC loss caused by the mutant gene in rat eyes.

    Evidence Allotopic expression in LHON patient fibroblasts with Complex I, ATP, and galactose growth assays; in vivo electroporation in rat eyes with RGC counting, neurite assays, and visual performance testing

    PMID:18513491 PMID:18771762

    Open questions at the time
    • Efficiency of mitochondrial import of allotopically expressed ND4 not quantified
    • Mechanism of protein insertion into assembled Complex I not characterized
  10. 2009 High

    AAV2-delivered allotopic ND4 was shown to be processed, imported into mitochondria, and physically incorporated into murine Complex I by immunoprecipitation, without compromising ATP synthesis or RGC survival—confirming biochemical integration of the transgene product into the respiratory chain.

    Evidence Intravitreal AAV2 injection in mice; immunoprecipitation of Complex I with FLAG detection; EM immunogold; ATP synthesis and pattern ERG

    PMID:19387075

    Open questions at the time
    • Stoichiometry of allotopic ND4 incorporation relative to endogenous subunit not determined
    • Whether allotopic ND4 fully replaces or supplements endogenous ND4 not resolved
  11. 2020 Medium

    In hiPSC-derived retinal ganglion cells from LHON patients, the ND4 mutation was shown to disrupt axonal mitochondrial transport via oxidative stress-mediated downregulation of KIF5A, and antioxidant treatment restored both KIF5A expression and mitochondrial motility, linking ND4 dysfunction to axonal transport pathology.

    Evidence Live imaging of mitochondrial transport in hiPSC-derived RGCs; KIF5A mRNA/protein quantification; N-acetyl-L-cysteine rescue

    PMID:32277753

    Open questions at the time
    • Whether KIF5A downregulation is the primary driver of RGC degeneration or a secondary effect not resolved
    • Mechanism linking ROS to KIF5A transcriptional regulation not identified
  12. 2021 High

    TMEM126A was identified as an assembly factor that specifically associates with newly synthesized ND4 and is required for incorporation of the ND4 module into the distal membrane arm of Complex I; the ND4-containing module remains TMEM126A-bound even during Complex I disassembly, establishing the modular assembly pathway.

    Evidence TMEM126A knockout; pulse-labeling interaction studies; quantitative proteomics; NDUFS3 depletion with native gel electrophoresis in two independent studies

    PMID:33879611 PMID:33882309

    Open questions at the time
    • Structural basis of TMEM126A-ND4 interaction not determined
    • Whether additional factors cooperate with TMEM126A for ND4 module insertion not fully explored
  13. 2023 Medium

    An alternative open reading frame within MT-ND4 was found to encode a 99-amino-acid polypeptide (MTALTND4) that localizes to mitochondria and cytoplasm and is detectable in plasma, suggesting the MT-ND4 locus is bicistronic.

    Evidence Bioinformatic identification; custom antibody immunoprecipitation from HeLa lysates; subcellular localization by microscopy

    PMID:37198654

    Open questions at the time
    • Specific molecular function of MTALTND4 not determined
    • Whether MTALTND4 contributes to Complex I biology or has an independent role is unknown
    • Independent replication with alternative antibodies needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key remaining questions include the structural basis for how ND4 coordinates NAD-linked substrate channeling to Complex I, the precise stoichiometry and mechanism of allotopic ND4 integration into pre-existing Complex I, and the physiological function of the alternative ORF product MTALTND4.
  • No high-resolution structure of human ND4 in the context of substrate channeling
  • Mechanism of allotopic ND4 insertion into assembled Complex I unknown
  • MTALTND4 function uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0005198 structural molecule activity 2 GO:0005215 transporter activity 1
Localization
GO:0005739 mitochondrion 5
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-1643685 Disease 4 R-HSA-5357801 Programmed Cell Death 2
Partners
KIF5ANDUFV2PHBTMEM126A
Complex memberships
Complex I (NADH:ubiquinone oxidoreductase)

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 The ND4/11778 mutation in the mitochondrial ND4 gene (encoding a subunit of Complex I) does not reduce rotenone-sensitive ubiquinone-dependent electron transfer activity or NADH dehydrogenase activity in inner mitochondrial membrane preparations, but does significantly decrease the rate of oxidation of NAD-linked substrates in isolated mitochondria, suggesting ND4 subunit is involved in specific aggregation of NADH-dependent dehydrogenases with Complex I for efficient electron transfer. Enzymatic assay of NADH:ubiquinone oxidoreductase in mitochondria from LHON patient cells; comparison of rotenone-sensitive activity, Km for NADH, and NAD-linked substrate oxidation rates FEBS letters High 1959619
1997 The 11778/ND4 mutation in homoplasmic platelets induces resistance to rotenone (a Complex I inhibitor) but does not markedly reduce specific Complex I activity, whereas the 3460/ND1 mutation causes both rotenone resistance and a marked decrease in Complex I specific activity; heteroplasmic individuals show normal biochemical features, indicating functional complementation by wild-type mtDNA. Enzymatic assay of Complex I activity and inhibitor sensitivity (rotenone, rolliniastatin-2) in mitochondrial particles from platelets, correlated with mtDNA sequence analysis Neurology High 9191778
1998 Modeling the human ND4/11778 mutation (Arg368His) in the homologous NuoM subunit of Rhodobacter capsulatus NDH-1 recapitulates the biochemical phenotype: reduced NADH-supported respiration in intact cells but not in isolated membranes, and no effect on proton-pump activity, establishing that the Arg368 residue of ND4 is critical for electron transfer but not proton translocation. Site-directed mutagenesis of NuoM (bacterial ND4 homolog) in Rhodobacter capsulatus; measurement of NADH-supported respiration and proton-pump activity in bacterial model Biochimica et biophysica acta High 9685604
2001 The yeast single-subunit NADH-quinone oxidoreductase (NDI1) can fully restore NADH dehydrogenase activity and galactose growth in human cells carrying a homoplasmic frameshift mutation in the ND4 gene, demonstrating that ND4 is essential for Complex I electron transfer activity and that its loss abolishes rotenone-sensitive, ubiquinone-dependent respiration. The restored respiration is rotenone-insensitive and flavone-sensitive, confirming the NDI1 protein localizes to mitochondria with its NADH-binding site facing the matrix. Complementation of ND4-null human cells (C4T line) with nuclear-encoded yeast NDI1; NADH dehydrogenase activity assays, respirometry, galactose growth assay, subcellular fractionation, P:O ratio measurement The Journal of biological chemistry High 11479321
2002 LHON cybrid cells harboring the 11778/ND4 mutation undergo apoptotic cell death when forced to rely on oxidative phosphorylation (galactose medium), with increased cytochrome c release into the cytosol, demonstrating that the ND4 mutation causes mitochondria-dependent apoptosis under metabolic stress. Cybrid cell lines; galactose-medium metabolic stress assay; chromatin condensation assay, DNA laddering, cytochrome c release by western blot The Journal of biological chemistry High 12446713
2004 In human cells lacking ND4 expression (but not ND5 or all ND subunits), the 24 kDa nuclear-encoded Complex I subunit fails to associate with the inner mitochondrial membrane while most other nuclear subunits remain membrane-attached, revealing that ND4 is specifically required for membrane attachment of the 24 kDa subunit and proper Complex I assembly. Additionally, prohibitin was found to interact with a Complex I subcomplex containing the 23, 30, and 49 kDa subunits. Fractionation of mitochondrial membranes from ND4-null, ND5-null, and rho0 human cell lines; western blot quantification of nuclear-encoded Complex I subunit distribution; immunopurification of subcomplexes The Biochemical journal High 15250827
2007 Conserved charged residues Glu144 and Lys234 in the transmembrane segments of E. coli NuoM (the ND4 homolog) are essential for energy-transducing NDH-1 activities (including proton translocation) but not for NADH dehydrogenase activity per se, and their mutation increases superoxide production; four conserved His residues are not essential for quinone binding. Site-directed mutagenesis of 15 residues in E. coli NuoM; measurement of NDH-1 energy-transducing activities, NADH dehydrogenase activity, superoxide production, and quinone Km/inhibitor IC50 The Journal of biological chemistry High 17977822
2007 Allotopic expression of the mutant human ND4 (R340H) in mouse retinal ganglion cells disrupts mitochondrial cytoarchitecture, elevates reactive oxygen species, induces optic nerve head swelling, and causes progressive apoptotic loss of retinal ganglion cells and their axons; wild-type human ND4 expressed in murine mitochondria causes no ocular toxicity. Allotopic gene delivery to mouse visual system using ATPc mitochondrial targeting sequence; MRI, immunohistochemistry, light and transmission electron microscopy, ROS measurement Investigative ophthalmology & visual science High 17197509
2008 Allotopic expression of wild-type ND4 (mRNA targeted to mitochondrial surface, protein imported into mitochondria) restores Complex I activity, ATP synthesis, and galactose growth in human fibroblasts from LHON patients harboring ND4 mutations, demonstrating that nuclear-encoded ND4 can functionally replace the mitochondrial gene product. Allotopic expression with mRNA localization to mitochondrial surface; Complex I enzymatic assay, ATP synthesis rate measurement, galactose growth assay in patient fibroblasts Biochimica et biophysica acta High 18513491
2008 Intravitreal electroporation of the human ND4 gene harboring the G11778A mutation into rat eyes causes degeneration of retinal ganglion cells (40% reduction), impairs RGC survival and neurite outgrowth in primary culture, and reduces visual performance; subsequent electroporation with wild-type ND4 prevents RGC loss and visual impairment. In vivo electroporation in rat eyes; RGC counting, primary cell culture survival and neurite assays, visual performance testing American journal of human genetics High 18771762
2009 AAV2-delivered allotopic human ND4 (fused to ATPc mitochondrial targeting sequence and FLAG epitope) is properly imported into mitochondria of mouse retinal ganglion cells and optic nerve axons after intravitreal injection, is incorporated into immunoprecipitated murine Complex I (detected as processed 52-kDa band), and does not reduce ATP synthesis rates or retinal ganglion cell counts. Intravitreal AAV2 injection; immunoprecipitation of murine Complex I followed by western blot for FLAG; confocal microscopy with mitochondrial dye colocalization; transmission electron microscopy with immunogold; ATP synthesis rate measurement; pattern ERG Investigative ophthalmology & visual science High 19387075
2021 TMEM126A (mutated in autosomal-recessive optic atrophy) associates with the newly synthesized mtDNA-encoded ND4 subunit of Complex I as revealed by pulse-labeling interaction studies, and its loss results in isolated Complex I deficiency; TMEM126A functions as an assembly factor specifically for the ND4 distal membrane module of Complex I, distinct from its paralogue TMEM126B which acts in ND2-module assembly. Genome editing (TMEM126A knockout); pulse-labeling interaction studies; quantitative proteomics; co-immunoprecipitation; Complex I activity assays Proceedings of the National Academy of Sciences of the United States of America High 33879611
2021 Ablation of NDUFS3 allows characterization of Complex I disassembly in a hierarchical, modular fashion; the ND4-containing module remains stable and bound to TMEM126A even during progressive Complex I degradation, further establishing TMEM126A as an ND4 module assembly factor. NDUFS3 depletion by genome editing; structural and functional analysis of Complex I disassembly by native gel electrophoresis and interaction studies; TMEM126A co-purification with ND4 module Cell reports High 33882309
2002 Differentiation of neuronal NT2 cells harboring the LHON 11778/ND4 mutation results in significantly increased reactive oxygen species production (abolished by rotenone, a Complex I inhibitor) compared to undifferentiated cells or controls, and reduces cell yield by 30%, indicating the neuronal environment uncovers the ROS-generating defect of the ND4 mutation in Complex I. Cybrid creation using neuronal NT2 precursor cells; ROS measurement before and after neuronal differentiation; rotenone inhibition; cell yield quantification; mitochondrial membrane potential measurement Human molecular genetics High 11854175
2023 An alternative open reading frame (altORF) within the human mitochondrial ND4 gene in the +3 reading frame encodes a 99-amino-acid polypeptide (MTALTND4) that localizes to both mitochondria and cytoplasm, is detectable in plasma, and impacts cell and mitochondrial physiology when manipulated; immunoprecipitation with a custom antibody confirmed endogenous MTALTND4 protein expression. Bioinformatic identification of altORF; custom antibody generation; immunoprecipitation from HeLa lysates; subcellular localization by microscopy; physiological impact assays BMC biology Medium 37198654
2020 In hiPSC-derived retinal ganglion cells from affected LHON patients (m.11778G>A MT-ND4), mitochondrial transport is altered with increased retrograde mitochondrial movement and decreased stationary mitochondria in axons; KIF5A protein and mRNA levels are significantly reduced in affected RGCs; antioxidant N-acetyl-L-cysteine restores KIF5A expression and normal mitochondrial movement, linking ND4 mutation-induced oxidative stress to disrupted mitochondrial transport via KIF5A. hiPSC-derived RGCs from affected patient, unaffected carrier, and control; live imaging of mitochondrial transport; KIF5A mRNA and protein quantification; NAC rescue experiment; ROS and apoptosis measurements Human molecular genetics Medium 32277753
2021 The mitomiR let-7a regulates mitochondrial transcription by interacting with mitochondrial DNA (including the ND4 gene region) as shown by RNA pull-down assays, and alters Complex I activity in a cell-line-specific manner in breast cancer cells. RNA pull-down assays; Complex I activity measurement; mitomiR let-7a overexpression in breast cancer cell lines Cancer cell international Low 34838007

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 The role of mtDNA background in disease expression: a new primary LHON mutation associated with Western Eurasian haplogroup J. Human genetics 178 11935318
2008 Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. American journal of human genetics 168 18771762
2002 Leber's hereditary optic neuropathy (LHON) pathogenic mutations induce mitochondrial-dependent apoptotic death in transmitochondrial cells incubated with galactose medium. The Journal of biological chemistry 161 12446713
1991 Electron transfer properties of NADH:ubiquinone reductase in the ND1/3460 and the ND4/11778 mutations of the Leber hereditary optic neuroretinopathy (LHON). FEBS letters 158 1959619
2002 Differentiation-specific effects of LHON mutations introduced into neuronal NT2 cells. Human molecular genetics 155 11854175
2016 Efficacy and Safety of rAAV2-ND4 Treatment for Leber's Hereditary Optic Neuropathy. Scientific reports 144 26892229
2004 Structural organization of mitochondrial human complex I: role of the ND4 and ND5 mitochondria-encoded subunits and interaction with prohibitin. The Biochemical journal 118 15250827
1997 Leber's hereditary optic neuropathy: biochemical effect of 11778/ND4 and 3460/ND1 mutations and correlation with the mitochondrial genotype. Neurology 106 9191778
2001 Lack of complex I activity in human cells carrying a mutation in MtDNA-encoded ND4 subunit is corrected by the Saccharomyces cerevisiae NADH-quinone oxidoreductase (NDI1) gene. The Journal of biological chemistry 102 11479321
2016 Dek35 Encodes a PPR Protein that Affects cis-Splicing of Mitochondrial nad4 Intron 1 and Seed Development in Maize. Molecular plant 100 27596292
2008 The optimized allotopic expression of ND1 or ND4 genes restores respiratory chain complex I activity in fibroblasts harboring mutations in these genes. Biochimica et biophysica acta 98 18513491
2019 Immune Response and Intraocular Inflammation in Patients With Leber Hereditary Optic Neuropathy Treated With Intravitreal Injection of Recombinant Adeno-Associated Virus 2 Carrying the ND4 Gene: A Secondary Analysis of a Phase 1/2 Clinical Trial. JAMA ophthalmology 90 30730541
2020 Visual Outcomes in Leber Hereditary Optic Neuropathy Patients With the m.11778G>A (MTND4) Mitochondrial DNA Mutation. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society 89 32969847
2011 LHON: Mitochondrial Mutations and More. Current genomics 89 21886454
2007 The mutant human ND4 subunit of complex I induces optic neuropathy in the mouse. Investigative ophthalmology & visual science 89 17197509
2006 Mitochondrial abnormalities in patients with LHON-like optic neuropathies. Investigative ophthalmology & visual science 89 17003408
2013 The pentatricopeptide repeat MTSF1 protein stabilizes the nad4 mRNA in Arabidopsis mitochondria. Nucleic acids research 87 23658225
1997 Wolfram (DIDMOAD) syndrome and Leber hereditary optic neuropathy (LHON) are associated with distinct mitochondrial DNA haplotypes. Genomics 85 9027481
1994 The maize NCS2 abnormal growth mutant has a chimeric nad4-nad7 mitochondrial gene and is associated with reduced complex I function. Genetics 84 7851780
2017 The Eye Drop Preservative Benzalkonium Chloride Potently Induces Mitochondrial Dysfunction and Preferentially Affects LHON Mutant Cells. Investigative ophthalmology & visual science 81 28444329
2007 Characterization of the NuoM (ND4) subunit in Escherichia coli NDH-1: conserved charged residues essential for energy-coupled activities. The Journal of biological chemistry 80 17977822
2006 A mutation in At-nMat1a, which encodes a nuclear gene having high similarity to group II intron maturase, causes impaired splicing of mitochondrial NAD4 transcript and altered carbon metabolism in Arabidopsis thaliana. Plant & cell physiology 75 16621844
2001 Novel mtDNA mutations and oxidative phosphorylation dysfunction in Russian LHON families. Human genetics 75 11479733
2005 LHON/MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation. European journal of human genetics : EJHG 71 15657614
2009 Efficiency and safety of AAV-mediated gene delivery of the human ND4 complex I subunit in the mouse visual system. Investigative ophthalmology & visual science 69 19387075
2023 Randomized trial of bilateral gene therapy injection for m.11778G>A MT-ND4 Leber optic neuropathy. Brain : a journal of neurology 68 36350566
1999 Exercise intolerance due to a nonsense mutation in the mtDNA ND4 gene. Annals of neurology 66 10360780
2012 Isolation of Arabidopsis ahg11, a weak ABA hypersensitive mutant defective in nad4 RNA editing. Journal of experimental botany 62 22821940
2011 A RESTORER OF FERTILITY-like PPR gene is required for 5'-end processing of the nad4 mRNA in mitochondria of Arabidopsis thaliana. The Plant journal : for cell and molecular biology 57 21251101
2015 Prevalence of Mitochondrial ND4 Mutations in 1281 Han Chinese Subjects With Leber's Hereditary Optic Neuropathy. Investigative ophthalmology & visual science 54 26218905
2000 Defective splicing of the first nad4 intron is associated with lack of several complex I subunits in the Nicotiana sylvestris NMS1 nuclear mutant. The Plant journal : for cell and molecular biology 54 10758478
2006 A novel missense mutation C11994T in the mitochondrial ND4 gene as a cause of low sperm motility in the Indian subcontinent. Fertility and sterility 52 17069814
2009 Extremely low penetrance of Leber's hereditary optic neuropathy in 8 Han Chinese families carrying the ND4 G11778A mutation. Ophthalmology 51 19167085
2003 Low penetrance of the 14484 LHON mutation when it arises in a non-haplogroup J mtDNA background. American journal of medical genetics. Part A 50 12749053
2016 Compound heterozygosity for severe and hypomorphic NDUFS2 mutations cause non-syndromic LHON-like optic neuropathy. Journal of medical genetics 46 28031252
2008 Mitochondrial variants may influence the phenotypic manifestation of Leber's hereditary optic neuropathy-associated ND4 G11778A mutation. Journal of genetics and genomics = Yi chuan xue bao 46 19022198
2005 Leber's hereditary optic neuropathy is associated with the mitochondrial ND4 G11696A mutation in five Chinese families. Biochemical and biophysical research communications 44 16364244
2016 Retinal Ganglion Cell and Inner Plexiform Layer Loss Correlate with Visual Acuity Loss in LHON: A Longitudinal, Segmentation OCT Analysis. Investigative ophthalmology & visual science 42 27459664
2011 Mitochondrial DNA haplogroup background affects LHON, but not suspected LHON, in Chinese patients. PloS one 42 22110754
2005 Isolation of transcriptomal changes attributable to LHON mutations and the cybridization process. Brain : a journal of neurology 42 15728653
2006 High penetrance of sequencing errors and interpretative shortcomings in mtDNA sequence analysis of LHON patients. Biochemical and biophysical research communications 41 17123466
1990 An example of Leber hereditary optic neuropathy not involving a mutation in the mitochondrial ND4 gene. American journal of human genetics 40 2121024
2020 Mitochondrial transport mediates survival of retinal ganglion cells in affected LHON patients. Human molecular genetics 39 32277753
2010 Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand. Human genetics 39 20407791
1996 Leber's hereditary optic neuropathy: heteroplasmy is likely to be significant in the expression of LHON in families with the 3460 ND1 mutation. The British journal of ophthalmology 39 8976705
2019 DEK43 is a P-type pentatricopeptide repeat (PPR) protein responsible for the Cis-splicing of nad4 in maize mitochondria. Journal of integrative plant biology 38 31119902
2005 A complete species-level phylogeny of the Hylobatidae based on mitochondrial ND3-ND4 gene sequences. Molecular phylogenetics and evolution 38 15950493
2021 Safety of Intravitreal Gene Therapy for Treatment of Subjects with Leber Hereditary Optic Neuropathy due to Mutations in the Mitochondrial ND4 Gene: The REVEAL Study. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy 37 33566264
2010 Induction of rapid and highly efficient expression of the human ND4 complex I subunit in the mouse visual system by self-complementary adeno-associated virus. Archives of ophthalmology (Chicago, Ill. : 1960) 36 20625049
2010 Very high penetrance and occurrence of Leber's hereditary optic neuropathy in a large Han Chinese pedigree carrying the ND4 G11778A mutation. Molecular genetics and metabolism 36 20627642
2016 The PPR protein SLOW GROWTH 4 is involved in editing of nad4 and affects the splicing of nad2 intron 1. Plant molecular biology 33 27942959
2021 MCAT Mutations Cause Nuclear LHON-like Optic Neuropathy. Genes 32 33918393
2019 Maize pentatricopeptide repeat protein DEK41 affects cis-splicing of mitochondrial nad4 intron 3 and is required for normal seed development. Journal of experimental botany 32 31020318
2015 The DYW Subgroup PPR Protein MEF35 Targets RNA Editing Sites in the Mitochondrial rpl16, nad4 and cob mRNAs in Arabidopsis thaliana. PloS one 32 26470017
2014 Temperature- and pressure-induced phase transitions in the metal formate framework of [ND₄][Zn(DCOO)₃] and [NH₄][Zn(HCOO)₃]. Inorganic chemistry 32 25147972
1993 Pitfalls in the molecular genetic diagnosis of Leber hereditary optic neuropathy (LHON). American journal of human genetics 32 8213820
2018 Mitochondrial DNA copy number in affected and unaffected LHON mutation carriers. BMC research notes 31 30572950
1996 Molecular phylogeny for marine turtles based on sequences of the ND4-leucine tRNA and control regions of mitochondrial DNA. Molecular phylogenetics and evolution 31 8744764
2010 Mitochondrial ND6 T14502C variant may modulate the phenotypic expression of LHON-associated G11778A mutation in four Chinese families. Biochemical and biophysical research communications 29 20691156
2020 The novel E-subgroup pentatricopeptide repeat protein DEK55 is responsible for RNA editing at multiple sites and for the splicing of nad1 and nad4 in maize. BMC plant biology 27 33297963
2009 Phylogenetic analysis of the Pacific cutthroat trout (Oncorhynchus clarki ssp.: Salmonidae) based on partial mtDNA ND4 sequences: a closer look at the highly fragmented inland species. Molecular phylogenetics and evolution 27 19341807
2013 Next-generation sequencing of mitochondrial targeted AAV transfer of human ND4 in mice. Molecular vision 26 23869167
2023 A small protein coded within the mitochondrial canonical gene nd4 regulates mitochondrial bioenergetics. BMC biology 25 37198654
2013 Mitochondrial haplotypes may modulate the phenotypic manifestation of the LHON-associated m.14484T>C (MT-ND6) mutation in Chinese families. Mitochondrion 25 23665487
2007 Mutation C11994T in the mitochondrial ND4 gene is not a cause of low sperm motility in Portugal. Fertility and sterility 25 17517394
2006 Colour vision defects in asymptomatic carriers of the Leber's hereditary optic neuropathy (LHON) mtDNA 11778 mutation from a large Brazilian LHON pedigree: a case-control study. The British journal of ophthalmology 25 16424523
2005 A novel mtDNA ND6 gene mutation associated with LHON in a Caucasian family. Biochemical and biophysical research communications 25 15922297
2009 Evidence of two lineages of the dengue vector Aedes aegypti in the Brazilian Amazon, based on mitochondrial DNA ND4 gene sequences. Genetics and molecular biology 24 21637700
2004 mtDNA/nDNA ratio in 14484 LHON mitochondrial mutation carriers. Journal of human genetics 24 15635488
1992 High frequency of mitochondrial ND4 gene mutation in Japanese pedigrees with Leber hereditary optic neuropathy. Japanese journal of ophthalmology 24 1635296
2021 NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate. Cell reports 23 33882309
2021 Let-7a induces metabolic reprogramming in breast cancer cells via targeting mitochondrial encoded ND4. Cancer cell international 23 34838007
2021 Mitochondrial Genome Study Identifies Association Between Primary Open-Angle Glaucoma and Variants in MT-CYB, MT-ND4 Genes and Haplogroups. Frontiers in genetics 23 34976016
2019 A Mitochondrial Transcription Termination Factor, ZmSmk3, Is Required for nad1 Intron4 and nad4 Intron1 Splicing and Kernel Development in Maize. G3 (Bethesda, Md.) 23 31196888
2007 Differential cerebro spinal fluid proteome investigation of Leber hereditary optic neuropathy (LHON) and multiple sclerosis. Journal of neuroimmunology 23 18061280
1976 Simian virus 40-specific polypeptides in AD2+ ND1- and Ad2+ ND4-infected cells. Journal of virology 23 178903
2006 Novel mitochondrial mutation in the ND4 gene associated with Leigh syndrome. Acta neurologica Scandinavica 22 17022785
2021 Optic atrophy-associated TMEM126A is an assembly factor for the ND4-module of mitochondrial complex I. Proceedings of the National Academy of Sciences of the United States of America 21 33879611
2012 Presence of mutation m.14484T>C in a Chinese family with maternally inherited essential hypertension but no expression of LHON. Biochimica et biophysica acta 21 22749828
2022 Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G>A MT-ND4 Mutation. Ophthalmology and therapy 20 36449262
2017 Genetic and Clinical Analyses of DOA and LHON in 304 Chinese Patients with Suspected Childhood-Onset Hereditary Optic Neuropathy. PloS one 20 28081242
2003 Sequence polymorphisms within the human mitochondrial genes MTATP6, MTATP8 and MTND4. International journal of legal medicine 20 12734709
2002 The sugar beet mitochondrial nad4 gene: an intron loss and its phylogenetic implication in the Caryophyllales. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 20 12582688
1998 The nuoM arg368his mutation in NADH:ubiquinone oxidoreductase from Rhodobacter capsulatus: a model for the human nd4-11778 mtDNA mutation associated with Leber's hereditary optic neuropathy. Biochimica et biophysica acta 20 9685604
2019 Three rare pathogenic mtDNA substitutions in LHON patients with low heteroplasmy. Mitochondrion 19 31669237
2019 Four novel mutations in the mitochondrial ND4 gene of complex I in patients with multiple sclerosis. Biomedical reports 19 31798871
2014 Mitochondrial haplotypes may modulate the phenotypic manifestation of the LHON-associated ND1 G3460A mutation in Chinese families. Journal of human genetics 19 24430572
2013 Haplogroup heterogeneity of LHON patients carrying the m.14484T>C mutation in India. Investigative ophthalmology & visual science 19 23674761
2004 Inner retinal contributions to the multifocal electroretinogram: patients with Leber's hereditary optic neuropathy (LHON). Multifocal ERG in patients with LHON. Documenta ophthalmologica. Advances in ophthalmology 19 15573947
2004 Segregation pattern and biochemical effect of the G3460A mtDNA mutation in 27 members of LHON family. Journal of the neurological sciences 18 15337616
2020 Diagnostic value of circulating cell-free mtDNA in patients with suspected thyroid cancer: ND4/ND1 ratio as a new potential plasma marker. Mitochondrion 17 33035689
2016 Male-specific association between MT-ND4 11719 A/G polymorphism and ulcerative colitis: a mitochondria-wide genetic association study. BMC gastroenterology 17 27716073
2016 Functional Characterization of Three Concomitant MtDNA LHON Mutations Shows No Synergistic Effect on Mitochondrial Activity. PloS one 16 26784702
2012 Applications of the method of high resolution melting analysis for diagnosis of Leber's disease and the three primary mutation spectrum of LHON in the Han Chinese population. Gene 16 23063736
2011 LHON/MELAS overlap mutation in ND1 subunit of mitochondrial complex I affects ubiquinone binding as revealed by modeling in Escherichia coli NDH-1. Biochimica et biophysica acta 16 22079202
2009 Novel A14841G mutation is associated with high penetrance of LHON/C4171A family. Biochemical and biophysical research communications 16 19555656
2002 Segregation of the ND4/11778 and the ND1/3460 mutations in four heteroplasmic LHON families. Journal of the neurological sciences 16 12409182
1989 Mitochondrial DNA of Chlamydomonas reinhardtii: the ND4 gene encoding a subunit of NADH dehydrogenase. Current genetics 16 2791036
2012 Adeno-associated virus-mediated gene delivery of the human ND4 complex I subunit in rabbit eyes. Clinical & experimental ophthalmology 15 22612072
2002 Visual recovery in a man with the rare combination of mtDNA 11778 LHON mutation and a MS-like disease after mitoxantrone therapy. Acta neurologica Scandinavica 15 12225323