Affinage

Showing MT-ND4 — ND4 is a alias.

MT-ND4

NADH-ubiquinone oxidoreductase chain 4 · UniProt P03905

Length
459 aa
Mass
51.6 kDa
Annotated
2026-06-10
100 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MT-ND4 encodes the mitochondrially-encoded ND4 subunit of respiratory chain Complex I (NADH:ubiquinone oxidoreductase), where it is essential for enzymatic activity: a homoplasmic ND4-null human cell line loses NADH dehydrogenase activity and the ability to grow on galactose, defects fully rescued by the single-subunit yeast NDI1 enzyme (PMID:11479321), and allotopic re-expression of wild-type ND4 restores Complex I activity, ATP synthesis, and galactose growth in patient fibroblasts (PMID:18513491). ND4 contributes specifically to the distal membrane arm: it is required for proper membrane association of the 24 kDa nuclear-encoded subunit (PMID:15250827), and its biogenesis is governed by the assembly factor TMEM126A, which binds newly synthesized ND4 and is needed for correct assembly of the ND4 distal membrane module (PMID:33879611, PMID:33882309). Functional studies of the pathogenic G11778A/R340H allele place the lesion in electron transfer rather than proton translocation: in a bacterial homolog (Rhodobacter nuoM) the equivalent mutation impairs NADH-supported respiration while leaving proton pumping intact (PMID:9685604), and mutant ND4 elevates Complex I-derived reactive oxygen species in neuronal cells (PMID:11854175). This oxidative dysfunction drives the optic neuropathy phenotype — mutant ND4 triggers retinal ganglion cell apoptosis and visual loss in animal and patient-derived models (PMID:17197509, PMID:18771762), acting in part through downregulation of KIF5A and impaired axonal mitochondrial transport, which is reversible by antioxidant treatment (PMID:32277753). The nd4 locus additionally encodes an alternative reading-frame polypeptide, MTALTND4, an endogenously expressed protein that localizes to mitochondria and cytoplasm and influences mitochondrial bioenergetics (PMID:37198654).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1991 Medium

    Established that the 11778/ND4 mutation does not simply abolish catalytic NADH dehydrogenase activity, reframing the defect as a kinetic/organizational impairment of NAD-linked substrate oxidation.

    Evidence Enzymatic assays of Complex I in membrane preparations versus isolated mitochondria from LHON patient cells

    PMID:1959619

    Open questions at the time
    • No molecular mechanism for how ND4 affects substrate-channeling kinetics
    • Single lab, patient-derived material only
  2. 1997 Medium

    Showed the ND4 mutation confers altered inhibitor sensitivity rather than loss of activity and is functionally complemented by wild-type mtDNA in heteroplasmic cells, distinguishing it biochemically from ND1 mutations.

    Evidence Complex I activity and rotenone/rolliniastatin-2 inhibitor profiling in platelet mitochondria correlated with mtDNA genotype

    PMID:9191778

    Open questions at the time
    • Does not define the structural basis of altered inhibitor binding
    • Threshold of heteroplasmy for biochemical rescue not resolved
  3. 1998 High

    Demonstrated in a tractable bacterial homolog that the 11778-equivalent position selectively impairs electron transfer and not proton pumping, localizing the functional role of this ND4 residue.

    Evidence Site-directed mutagenesis of nuoM in Rhodobacter capsulatus with respiration, growth, and proton-pump assays

    PMID:9685604

    Open questions at the time
    • Bacterial NuoM is a homolog, not the human protein
    • Does not address neuron-specific manifestation
  4. 2001 High

    Proved ND4 is essential for human Complex I NADH:ubiquinone oxidoreductase activity by rescuing an ND4-null cell line with the single-subunit yeast NDI1 enzyme.

    Evidence NDI1 complementation of human ND4-null cells with enzymatic, growth, P:O ratio, and topology assays

    PMID:11479321

    Open questions at the time
    • NDI1 bypasses rather than reconstitutes native ND4 chemistry
    • Does not resolve ND4's specific contribution within the holoenzyme
  5. 2004 Medium

    Defined a specific assembly role for ND4 by showing it is required for membrane association of the 24 kDa nuclear-encoded subunit.

    Evidence Membrane fractionation and immunoblotting of ND4-null human cells; subcomplex immunopurification

    PMID:15250827

    Open questions at the time
    • Mechanism of how ND4 stabilizes the 24 kDa subunit not defined
    • Prohibitin interaction not mechanistically linked to ND4
  6. 2002 Medium

    Linked mutant ND4 to elevated Complex I-derived superoxide and showed the phenotype requires a differentiated neuronal context, explaining tissue-selective pathology.

    Evidence Cybrid neuronal cell model with ROS measurement and rotenone inhibition

    PMID:11854175

    Open questions at the time
    • Cybrid background may not fully recapitulate neuronal physiology
    • Source of differentiation-dependence not molecularly defined
  7. 2008 High

    Established a causal link between mutant ND4 and retinal ganglion cell degeneration that is preventable by wild-type ND4, validating ND4 dysfunction as the disease driver and the basis for gene therapy.

    Evidence In vivo allotopic expression of mutant and wild-type ND4 in rat eyes plus patient fibroblast rescue with growth/ATP/activity readouts

    PMID:17197509 PMID:18513491 PMID:18771762

    Open questions at the time
    • Allotopic expression is non-physiological relative to native mitochondrial translation
    • Does not resolve the downstream death pathway
  8. 2015 High

    Confirmed allotopically delivered ND4 is imported and assembles into endogenous Complex I, restoring function in vivo and supporting therapeutic feasibility.

    Evidence AAV ocular delivery with immunoprecipitation of Complex I-incorporated human ND4 and functional rescue in rat and mouse models

    PMID:19387075 PMID:26029714

    Open questions at the time
    • Long-term durability and efficiency of import not fully quantified
    • Does not address assembly route of natively translated ND4
  9. 2021 High

    Identified TMEM126A as the dedicated assembly factor that binds newly synthesized ND4 and builds the ND4 distal membrane module, providing the biogenesis mechanism for this subunit.

    Evidence TMEM126A knockout, pulse-labeling Co-IP of newly synthesized ND4, BN-PAGE assembly intermediates, and NDUFS3-depletion disassembly mapping

    PMID:33879611 PMID:33882309

    Open questions at the time
    • Structural detail of the TMEM126A–ND4 interaction not resolved
    • Order of subunit recruitment within the module not fully ordered
  10. 2020 Medium

    Connected mutant ND4 oxidative dysfunction to a concrete neuronal pathomechanism: KIF5A downregulation impairing axonal mitochondrial transport, reversible by antioxidant.

    Evidence hiPSC-derived retinal ganglion cells from m.11778G>A carriers with live mitochondrial-transport imaging, KIF5A quantification, and NAC rescue

    PMID:32277753

    Open questions at the time
    • Molecular link between ROS and KIF5A transcription not defined
    • Single lab, patient-derived model
  11. 2023 Medium

    Revealed that the nd4 locus encodes an additional functional polypeptide, MTALTND4, expanding the coding output of the gene and its influence on bioenergetics.

    Evidence Endogenous protein confirmation by immunoprecipitation from HeLa lysates, subcellular localization, and functional bioenergetic assays

    PMID:37198654

    Open questions at the time
    • Molecular mechanism of MTALTND4 action unknown
    • Relationship to ND4 subunit function not established
  12. 2017 Low

    Identified ND4 as a hormonally regulated mitochondrial gene, with testosterone modulating its expression and Complex I activity in dopaminergic neurons.

    Evidence Castration and testosterone supplementation rat model with ND4 expression and Complex I activity measurement in substantia nigra

    PMID:29138672

    Open questions at the time
    • No molecular mechanism linking testosterone to ND4 transcription
    • Single lab, correlative expression/activity readouts only

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ND4 contributes structurally to electron transfer within the assembled holoenzyme, and how the ROS-to-KIF5A axis is molecularly wired, remain unresolved.
  • No high-resolution structural mechanism for the R340H electron-transfer defect
  • Transcriptional/signaling link between Complex I ROS and KIF5A undefined
  • Native (non-allotopic) ND4 assembly sequence not fully mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 2 GO:0140098 catalytic activity, acting on RNA 1
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-1430728 Metabolism 2
Partners
NDUFS3TMEM126A
Complex memberships
Mitochondrial respiratory chain Complex I

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 The ND4/11778A mutation in human mitochondrial DNA does not reduce rotenone-sensitive electron transfer activity or NADH dehydrogenase activity of Complex I in inner mitochondrial membrane preparations, nor does it affect Km for NADH; however, in isolated mitochondria carrying the ND4 mutation, the rate of oxidation of NAD-linked substrates (but not succinate) is significantly decreased, suggesting the ND4 subunit may be involved in specific aggregation of NADH-dependent dehydrogenases and Complex I for fast 'solid state' electron transfer. Enzymatic assay of NADH:ubiquinone oxidoreductase activity in mitochondria from LHON patient cells; comparison of rotenone-sensitive/ubiquinone-dependent electron transfer and NADH dehydrogenase activity in membrane preparations vs. isolated mitochondria FEBS letters Medium 1959619
1997 In platelets homoplasmic for the 11778/ND4 mtDNA mutation, Complex I exhibits resistance to the inhibitors rotenone and rolliniastatin-2, whereas the 3460/ND1 mutation additionally causes a marked decrease in specific Complex I activity. Individuals heteroplasmic for either mutation show normal biochemical features, indicating functional complementation by wild-type mtDNA. Enzymatic assay of mitochondrial Complex I activity and inhibitor sensitivity (rotenone, rolliniastatin-2) in mitochondrial particles from platelets; correlation with mtDNA genotyping Neurology Medium 9191778
1998 Introduction of the nuoM-1103 point mutation in Rhodobacter capsulatus (reproducing the human nd4-11778 mutation in the homologous NUOM subunit) impairs NADH-supported respiration and oxidative phosphorylation capacity in porous cells but does not reduce proton-pump activity, mirroring the biochemical features seen in human mitochondria with the nd4-11778 mutation and indicating that the nd4-11778 position affects electron transfer rather than proton translocation. Bacterial genetics (site-directed mutagenesis of nuoM gene in Rhodobacter capsulatus); NADH-supported respiration assay in porous cells; growth on malate medium; measurement of proton-pump activity in isolated bacterial membranes Biochimica et biophysica acta High 9685604
2001 The yeast single-subunit NADH-quinone oxidoreductase (NDI1) can fully restore NADH dehydrogenase activity and galactose-medium growth in human cells carrying a homoplasmic frameshift mutation in the ND4 gene. The yeast NDI1 protein localizes to human mitochondria with its NADH-binding site facing the matrix, couples to the downstream human respiratory chain (antimycin A-sensitive), and its P:O ratio is approximately two-thirds of wild-type, consistent with lack of proton pumping — demonstrating that ND4 is essential for human Complex I NADH:ubiquinone oxidoreductase activity. Complementation assay: nuclear transfection of yeast NDI1 into human ND4-null cells (C4T cell line); NADH dehydrogenase activity assay; galactose growth rescue; P:O ratio measurement; subcellular fractionation and topology determination The Journal of biological chemistry High 11479321
2002 LHON-NT2 neuronal cells differentiated from the NT2 precursor cell line and carrying the 11778/ND4 mutation produce significantly increased reactive oxygen species (ROS) compared to controls; this increase is abolished by rotenone (Complex I inhibitor), indicating that the mutant ND4-containing Complex I is the source of excess mitochondrial superoxide. The LHON genotype requires a differentiated neuronal environment to manifest increased ROS. Cybrid cell model (NT2 neuronal precursor cells fused with patient lymphoblast mitochondria carrying 11778 mutation); ROS measurement before and after differentiation; rotenone inhibition; mtDNA/nDNA ratio; mitochondrial membrane potential; Alamar Blue reduction Human molecular genetics Medium 11854175
2004 In human cells lacking ND4 expression, very low amounts of the 24 kDa nuclear-encoded Complex I subunit associate with the mitochondrial inner membrane (while most other nuclear-encoded subunits remain membrane-attached), revealing that ND4 is specifically required for proper membrane association of the 24 kDa subunit as part of Complex I assembly. Additionally, immunopurification identified a subcomplex containing the 23, 30, and 49 kDa subunits that also contains prohibitin, the first description of prohibitin interaction with Complex I subunits. Membrane fractionation and immunoblotting of ND4-null, ND5-null, and rho-zero human cell lines vs. controls; analysis of nuclear-encoded Complex I subunit distribution; immunopurification of subcomplexes The Biochemical journal Medium 15250827
2007 Allotopic expression of the mutant human ND4 subunit (R340H substitution, equivalent to the G11778A LHON mutation) directed to mitochondria via an ATPc targeting sequence in the mouse visual system disrupts mitochondrial cytoarchitecture, elevates reactive oxygen species, induces swelling of the optic nerve head, and triggers progressive apoptosis of retinal ganglion cells and their axons — replicating LHON pathology. Expression of wild-type human ND4 in the same system causes no toxicity. Allotopic expression via intravitreal injection of AAV vector in mice; MRI; immunohistochemistry; light and transmission electron microscopy; ROS measurement; retinal ganglion cell quantification Investigative ophthalmology & visual science High 17197509
2008 Optimized allotopic expression of wild-type ND4 (nuclear-encoded mRNA with mitochondrial surface targeting) rescues Complex I activity, ATP synthesis rate, and ability to grow on galactose in skin fibroblasts from LHON patients harboring ND4 mutations. The rescue is achieved with small amounts of hybrid mRNA/fusion protein, demonstrating efficient mitochondrial import of the allotopically expressed ND4 protein. Allotopic expression in patient fibroblasts; galactose growth assay; ATP synthesis rate measurement; Complex I enzymatic activity assay Biochimica et biophysica acta High 18513491
2008 Allotopic expression of wild-type ND4 in rat eyes (via electroporation) prevents retinal ganglion cell (RGC) loss and impairment of visual function caused by prior introduction of the G11778A mutant ND4. Introduction of mutant ND4 alone causes ~40% RGC loss, reduced neurite outgrowth in primary culture, and visual performance decline, establishing a causal role for mutant ND4 in RGC degeneration. In vivo electroporation of rat eyes with mutant or wild-type ND4 constructs; RGC counting; primary RGC culture survival and neurite outgrowth assays; visual performance testing American journal of human genetics High 18771762
2009 AAV2-mediated allotopic delivery of a nuclear-encoded human ND4 subunit (fused to ATPc mitochondrial targeting sequence and FLAG epitope) results in proper processing and import of the protein into mitochondria of mouse retinal ganglion cells and optic nerve axons. Immunoprecipitated murine Complex I contains the processed human ND4FLAG (52 kDa). ATP synthesis rates and pattern ERG amplitudes are maintained, indicating safe incorporation into the endogenous Complex I without toxicity. Intravitreal AAV2 injection; immunoprecipitation of Complex I with detection of human ND4FLAG; confocal microscopy with mitochondrial marker colocalization; transmission electron microscopy with immunogold; ATP synthesis rate; pattern electroretinography; RGC quantification Investigative ophthalmology & visual science High 19387075
2015 Allotopically expressed human ND4 (delivered by recombinant AAV vector to rat eyes) is efficiently imported into mitochondria and assembles into respiratory chain Complex I. In the rat LHON model, the human ND4 protein in optic nerves preserves Complex I function and significantly prevents retinal ganglion cell degeneration and visual function loss. Recombinant AAV ocular administration; immunocytochemistry confirming mitochondrial import; Complex I activity assay in optic nerves; retinal ganglion cell counting; visual function testing Molecular therapy. Methods & clinical development High 26029714
2021 TMEM126A, encoded by a gene mutated in autosomal-recessive optic atrophy, is an assembly factor that associates with the newly synthesized mtDNA-encoded ND4 subunit of Complex I (shown by pulse-labeling interaction studies) and is required for correct assembly and function of the ND4 distal membrane module of Complex I. Loss of TMEM126A causes isolated Complex I deficiency. Its function is distinct from its paralogue TMEM126B, which acts in ND2-module assembly. Genome editing (TMEM126A knockout); quantitative proteomics; Co-immunoprecipitation/interaction studies; pulse-labeling of newly synthesized ND4; blue native PAGE for Complex I assembly intermediates; respiratory chain activity assays Proceedings of the National Academy of Sciences of the United States of America High 33879611
2021 Ablation of NDUFS3 (a non-catalytic Complex I core subunit) reveals that the ND4 module of Complex I remains stable during hierarchical disassembly and that this stable ND4-module intermediate is bound by TMEM126A, establishing TMEM126A as an assembly factor for the ND4 module. NDUFS3 depletion (siRNA/KO) in mammalian cells; blue native PAGE analysis of Complex I disassembly intermediates; interaction studies identifying TMEM126A bound to ND4-module Cell reports High 33882309
2023 An alternative open reading frame (altORF) in the +3 reading frame of the human mitochondrial nd4 gene encodes a 99-amino-acid polypeptide (MTALTND4), conserved in primates. Endogenous MTALTND4 protein was confirmed by immunoprecipitation from HeLa cell lysates using a custom antibody. The protein localizes to both mitochondria and cytoplasm and is also found in plasma; its expression impacts cell and mitochondrial physiology (bioenergetics). Custom antibody immunoprecipitation from HeLa lysates confirming endogenous protein; subcellular fractionation/localization; functional assays of mitochondrial physiology upon altORF modulation BMC biology Medium 37198654
2020 In hiPSC-derived retinal ganglion cells from LHON-affected patients carrying the m.11778G>A MT-ND4 mutation, mitochondrial transport in axons is altered (increased retrograde movement, decreased stationary mitochondria) compared to unaffected carriers, and KIF5A mRNA and protein levels are significantly reduced. Antioxidant N-acetyl-L-cysteine restores KIF5A expression and normalizes the mitochondrial transport pattern, indicating that oxidative stress from mutant MT-ND4-driven Complex I dysfunction acts through KIF5A to impair anterograde mitochondrial transport in affected neurons. hiPSC-derived retinal ganglion cells from affected and unaffected m.11778G>A carriers; live-cell mitochondrial transport imaging; mRNA and protein quantification of KIF5A; ROS measurement; apoptosis assay; NAC rescue experiment Human molecular genetics Medium 32277753
2017 Castration (testosterone deficiency) in male rats reduces mitochondrial Complex I activity in the substantia nigra and downregulates the expression of both ND1 and ND4 subunits among the seven mtDNA-encoded Complex I subunits. Testosterone propionate supplementation to castrated rats restores Complex I activity and upregulates ND1 and ND4 expression, identifying ND4 as a testosterone-responsive mitochondrial gene in the nigrostriatal dopaminergic system. Orchiectomy rat model with testosterone propionate rescue; Complex I activity assay; quantitative measurement of ND1 and ND4 expression levels in substantia nigra Oxidative medicine and cellular longevity Low 29138672

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 169 18771762
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 147 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
2006 The novel A4435G mutation in the mitochondrial tRNAMet may modulate the phenotypic expression of the LHON-associated ND4 G11778A mutation. Investigative ophthalmology & visual science 109 16431939
1997 Leber's hereditary optic neuropathy: biochemical effect of 11778/ND4 and 3460/ND1 mutations and correlation with the mitochondrial genotype. Neurology 106 9191778
2016 Dek35 Encodes a PPR Protein that Affects cis-Splicing of Mitochondrial nad4 Intron 1 and Seed Development in Maize. Molecular plant 102 27596292
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
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
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 92 32969847
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 92 30730541
2011 LHON: Mitochondrial Mutations and More. Current genomics 91 21886454
2007 The mutant human ND4 subunit of complex I induces optic neuropathy in the mouse. Investigative ophthalmology & visual science 90 17197509
2006 Mitochondrial abnormalities in patients with LHON-like optic neuropathies. Investigative ophthalmology & visual science 89 17003408
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 85 7851780
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
2023 Randomized trial of bilateral gene therapy injection for m.11778G>A MT-ND4 Leber optic neuropathy. Brain : a journal of neurology 70 36350566
2015 Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss. Molecular therapy. Methods & clinical development 70 26029714
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
2018 Leber's hereditary optic neuropathy (LHON)-associated ND5 12338T > C mutation altered the assembly and function of complex I, apoptosis and mitophagy. Human molecular genetics 66 29579248
2003 LHON and other optic nerve atrophies: the mitochondrial connection. Developments in ophthalmology 65 12876832
2014 LHON gene therapy vector prevents visual loss and optic neuropathy induced by G11778A mutant mitochondrial DNA: biodistribution and toxicology profile. Investigative ophthalmology & visual science 59 25342621
2006 The mitochondrial tRNA(Thr) A15951G mutation may influence the phenotypic expression of the LHON-associated ND4 G11778A mutation in a Chinese family. Gene 58 16624503
2021 Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison. Frontiers in neurology 55 34108929
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
2000 'Secondary' 4216/ND1 and 13708/ND5 Leber's hereditary optic neuropathy mitochondrial DNA mutations do not further impair in vivo mitochondrial oxidative metabolism when associated with the 11778/ND4 mitochondrial DNA mutation. Brain : a journal of neurology 53 10960053
2009 Extremely low penetrance of Leber's hereditary optic neuropathy in 8 Han Chinese families carrying the ND4 G11778A mutation. Ophthalmology 51 19167085
2006 Cosegregation of the ND4 G11696A mutation with the LHON-associated ND4 G11778A mutation in a four generation Chinese family. Mitochondrion 49 17300996
2016 Compound heterozygosity for severe and hypomorphic NDUFS2 mutations cause non-syndromic LHON-like optic neuropathy. Journal of medical genetics 47 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
2005 Isolation of transcriptomal changes attributable to LHON mutations and the cybridization process. Brain : a journal of neurology 43 15728653
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
2007 The expression of the mitochondrial gene MT-ND4 is downregulated in cystic fibrosis. Biochemical and biophysical research communications 41 17382898
2006 High penetrance of sequencing errors and interpretative shortcomings in mtDNA sequence analysis of LHON patients. Biochemical and biophysical research communications 41 17123466
2020 Mitochondrial transport mediates survival of retinal ganglion cells in affected LHON patients. Human molecular genetics 40 32277753
1990 An example of Leber hereditary optic neuropathy not involving a mutation in the mitochondrial ND4 gene. American journal of human genetics 40 2121024
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 39 31119902
2017 Testosterone Upregulates the Expression of Mitochondrial ND1 and ND4 and Alleviates the Oxidative Damage to the Nigrostriatal Dopaminergic System in Orchiectomized Rats. Oxidative medicine and cellular longevity 39 29138672
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
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 38 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
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 35 31020318
2010 Mitochondrial haplogroup M9a specific variant ND1 T3394C may have a modifying role in the phenotypic expression of the LHON-associated ND4 G11778A mutation. Molecular genetics and metabolism 35 20728388
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
2018 Mitochondrial DNA copy number in affected and unaffected LHON mutation carriers. BMC research notes 32 30572950
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
1999 Alteration of dark respiration and reduction of phototrophic growth in a mitochondrial DNA deletion mutant of Chlamydomonas lacking cob, nd4, and the 3' end of nd5. The Plant cell 32 9878636
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
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 29 33297963
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
2023 A small protein coded within the mitochondrial canonical gene nd4 regulates mitochondrial bioenergetics. BMC biology 28 37198654
1997 LHON mutations in Italian patients affected by multiple sclerosis. Acta neurologica Scandinavica 28 9300066
2013 Next-generation sequencing of mitochondrial targeted AAV transfer of human ND4 in mice. Molecular vision 27 23869167
2021 Dysfunction in Mitochondrial Electron Transport Chain Complex I, Pyruvate Dehydrogenase Activity, and Mutations in ND1 and ND4 Gene in Autism Spectrum Disorder Subjects from Tamil Nadu Population, India. Molecular neurobiology 26 34279772
2019 A Mitochondrial Transcription Termination Factor, ZmSmk3, Is Required for nad1 Intron4 and nad4 Intron1 Splicing and Kernel Development in Maize. G3 (Bethesda, Md.) 26 31196888
2005 The role of the ND5 gene in LHON: characterization of a new, heteroplasmic LHON mutation. Annals of neurology 26 16240359
2013 Mitochondrial haplotypes may modulate the phenotypic manifestation of the LHON-associated m.14484T>C (MT-ND6) mutation in Chinese families. Mitochondrion 25 23665487
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
2002 Leber's hereditary optic neuropathy: clinical and molecular genetic results in a patient with a point mutation at np T11253C (isoleucine to threonine) in the ND4 gene and spontaneous recovery. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 25 12271374
2021 NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate. Cell reports 24 33882309
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
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 23 36449262
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
2016 Characterization of a Leber's hereditary optic neuropathy (LHON) family harboring two primary LHON mutations m.11778G>A and m.14484T>C of the mitochondrial DNA. Mitochondrion 23 27721048
2010 Mitochondrial DNA sequence variation and haplogroup distribution in Chinese patients with LHON and m.14484T>C. PloS one 23 20976138
2009 Confirmation of the mitochondrial ND1 gene mutation G3635A as a primary LHON mutation. Biochemical and biophysical research communications 23 19497304
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
2019 Leber hereditary optic neuropathy plus dystonia, and transverse myelitis due to double mutations in MT-ND4 and MT-ND6. Journal of neurology 20 31776719
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
2020 Diagnostic value of circulating cell-free mtDNA in patients with suspected thyroid cancer: ND4/ND1 ratio as a new potential plasma marker. Mitochondrion 18 33035689
2019 Ketogenic treatment reduces the percentage of a LHON heteroplasmic mutation and increases mtDNA amount of a LHON homoplasmic mutation. Orphanet journal of rare diseases 18 31226990
2004 Segregation pattern and biochemical effect of the G3460A mtDNA mutation in 27 members of LHON family. Journal of the neurological sciences 18 15337616
2016 Male-specific association between MT-ND4 11719 A/G polymorphism and ulcerative colitis: a mitochondria-wide genetic association study. BMC gastroenterology 17 27716073
2014 Profiling the mitochondrial proteome of Leber's Hereditary Optic Neuropathy (LHON) in Thailand: down-regulation of bioenergetics and mitochondrial protein quality control pathways in fibroblasts with the 11778G>A mutation. PloS one 17 25215595
2012 Nonsynonymous variants in mt-Nd2, mt-Nd4, and mt-Nd5 are linked to effects on oxidative phosphorylation and insulin sensitivity in rat conplastic strains. Physiological genomics 17 22414913
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 17 22079202
1999 Phylogeny and evolution of the Drosophila nasuta subgroup based on mitochondrial ND4 and ND4L gene sequences. Molecular phylogenetics and evolution 17 10620413
2002 Segregation of the ND4/11778 and the ND1/3460 mutations in four heteroplasmic LHON families. Journal of the neurological sciences 16 12409182

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