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NADH dehydrogenase (ubiquinone) Fe-S protein 4, 18kDa (NADH-coenzyme Q reductase)
Symbols NDUFS4 ; AQDQ; CI-18
External IDs OMIM602694 MGI1343135 HomoloGene1866 GeneCards: NDUFS4 Gene
RNA expression pattern
PBB GE NDUFS4 209303 at tn.png
More reference expression data
Species Human Mouse
Entrez 4724 17993
Ensembl ENSG00000164258 ENSMUSG00000021764
UniProt O43181 Q9CXZ1
RefSeq (mRNA) NM_002495 NM_010887
RefSeq (protein) NP_002486 NP_035017
Location (UCSC) Chr 5:
52.86 – 52.98 Mb
Chr 13:
114.29 – 114.39 Mb
PubMed search [1] [2]

NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial also known as NADH-ubiquinone oxidoreductase 18 kDa subunit is an enzyme that in humans is encoded by the NDUFS4 gene.[1][2][3]


Complex I, or NADH:ubiquinone oxidoreductase, the first multisubunit enzyme complex of the mitochondrial respiratory chain chain, plays a vital role in cellular ATP production, the primary source of energy for many crucial processes in living cells. It removes electrons from NADH and passes them by a series of different protein-coupled redox centers to the electron acceptor ubiquinone. In well-coupled mitochondria, the electron flux leads to ATP generation via the building of a proton gradient across the inner membrane. Complex I is composed of at least 41 subunits, of which 7 are encoded by the mitochondrial genome (ND1-6, ND4L) and the remainder by nuclear genes.[3][1]

Clinical significance[edit]

Mutations in the ACAD9 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders.[4][5] Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible.[6] However, the majority of cases are caused by mutations in nuclear-encoded genes.[7][8] It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.[9]Complex I deficiency with autosomal recessive inheritance results from mutation in nuclear-encoded subunit genes, including NDUFV1, NDUFV2, NDUFS1, NDUFS2, NDUFS3, NDUFS6, NDUFS7, NDUFS8, NDUFA2, NDUFA11, NDUFAF3, NDUFAF10, NDUFB3, NDUFB9, ACAD9, FOXRED1, and MTFMT.


  1. ^ a b van den Heuvel L, Ruitenbeek W, Smeets R, Gelman-Kohan Z, Elpeleg O, Loeffen J et al. (Feb 1998). "Demonstration of a new pathogenic mutation in human complex I deficiency: a 5-bp duplication in the nuclear gene encoding the 18-kD (AQDQ) subunit". American Journal of Human Genetics 62 (2): 262–8. doi:10.1086/301716. PMC 1376892. PMID 9463323. 
  2. ^ Emahazion T, Beskow A, Gyllensten U, Brookes AJ (Nov 1998). "Intron based radiation hybrid mapping of 15 complex I genes of the human electron transport chain". Cytogenetics and Cell Genetics 82 (1-2): 115–9. doi:10.1159/000015082. PMID 9763677. 
  3. ^ a b "Entrez Gene: NDUFS4 NADH dehydrogenase (ubiquinone) Fe-S protein 4, 18kDa (NADH-coenzyme Q reductase)". 
  4. ^ Kirby DM, Salemi R, Sugiana C, Ohtake A, Parry L, Bell KM et al. (Sep 2004). "NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency". The Journal of Clinical Investigation 114 (6): 837–45. doi:10.1172/JCI20683. PMID 15372108. 
  5. ^ McFarland R, Kirby DM, Fowler KJ, Ohtake A, Ryan MT, Amor DJ et al. (Jan 2004). "De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency". Annals of Neurology 55 (1): 58–64. doi:10.1002/ana.10787. PMID 14705112. 
  6. ^ Haack TB, Haberberger B, Frisch EM, Wieland T, Iuso A, Gorza M et al. (Apr 2012). "Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing". Journal of Medical Genetics 49 (4): 277–83. doi:10.1136/jmedgenet-2012-100846. PMID 22499348. 
  7. ^ Loeffen JL, Smeitink JA, Trijbels JM, Janssen AJ, Triepels RH, Sengers RC et al. (2000). "Isolated complex I deficiency in children: clinical, biochemical and genetic aspects". Human Mutation 15 (2): 123–34. doi:10.1002/(SICI)1098-1004(200002)15:2<123::AID-HUMU1>3.0.CO;2-P. PMID 10649489. 
  8. ^ Triepels RH, Van Den Heuvel LP, Trijbels JM, Smeitink JA (NaN). "Respiratory chain complex I deficiency". American Journal of Medical Genetics 106 (1): 37–45. doi:10.1002/ajmg.1397. PMID 11579423.  Check date values in: |date= (help)
  9. ^ Robinson BH (May 1998). "Human complex I deficiency: clinical spectrum and involvement of oxygen free radicals in the pathogenicity of the defect". Biochimica Et Biophysica Acta 1364 (2): 271–86. PMID 9593934. 

Further reading[edit]

  • Papa S, Sardanelli AM, Scacco S, Petruzzella V, Technikova-Dobrova Z, Vergari R et al. (Feb 2002). "The NADH: ubiquinone oxidoreductase (complex I) of the mammalian respiratory chain and the cAMP cascade". Journal of Bioenergetics and Biomembranes 34 (1): 1–10. doi:10.1023/A:1013863018115. PMID 11860175. 
  • Pilkington SJ, Skehel JM, Gennis RB, Walker JE (Feb 1991). "Relationship between mitochondrial NADH-ubiquinone reductase and a bacterial NAD-reducing hydrogenase". Biochemistry 30 (8): 2166–75. doi:10.1021/bi00222a021. PMID 1900194. 
  • Loeffen JL, Triepels RH, van den Heuvel LP, Schuelke M, Buskens CA, Smeets RJ et al. (Dec 1998). "cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase: human complex I cDNA characterization completed". Biochemical and Biophysical Research Communications 253 (2): 415–22. doi:10.1006/bbrc.1998.9786. PMID 9878551. 
  • Triepels RH, Hanson BJ, van den Heuvel LP, Sundell L, Marusich MF, Smeitink JA et al. (Mar 2001). "Human complex I defects can be resolved by monoclonal antibody analysis into distinct subunit assembly patterns". The Journal of Biological Chemistry 276 (12): 8892–7. doi:10.1074/jbc.M009903200. PMID 11112787. 
  • Papa S, Scacco S, Sardanelli AM, Vergari R, Papa F, Budde S et al. (Feb 2001). "Mutation in the NDUFS4 gene of complex I abolishes cAMP-dependent activation of the complex in a child with fatal neurological syndrome". FEBS Letters 489 (2-3): 259–62. doi:10.1016/S0014-5793(00)02334-6. PMID 11165261. 
  • Petruzzella V, Vergari R, Puzziferri I, Boffoli D, Lamantea E, Zeviani M et al. (Mar 2001). "A nonsense mutation in the NDUFS4 gene encoding the 18 kDa (AQDQ) subunit of complex I abolishes assembly and activity of the complex in a patient with Leigh-like syndrome". Human Molecular Genetics 10 (5): 529–35. doi:10.1093/hmg/10.5.529. PMID 11181577. 
  • Roef MJ, Reijngoud DJ, Jeneson JA, Berger R, de Meer K (Apr 2002). "Resting oxygen consumption and in vivo ADP are increased in myopathy due to complex I deficiency". Neurology 58 (7): 1088–93. doi:10.1212/wnl.58.7.1088. PMID 11940698. 
  • Lee BH, Lee H, Xiong L, Zhu JK (Jun 2002). "A mitochondrial complex I defect impairs cold-regulated nuclear gene expression". The Plant Cell 14 (6): 1235–51. doi:10.1105/tpc.010433. PMC 150777. PMID 12084824. 
  • Papa S (Sep 2002). "The NDUFS4 nuclear gene of complex I of mitochondria and the cAMP cascade". Biochimica Et Biophysica Acta 1555 (1-3): 147–53. doi:10.1016/S0005-2728(02)00270-0. PMID 12206907. 
  • Bénit P, Steffann J, Lebon S, Chretien D, Kadhom N, de Lonlay P et al. (May 2003). "Genotyping microsatellite DNA markers at putative disease loci in inbred/multiplex families with respiratory chain complex I deficiency allows rapid identification of a novel nonsense mutation (IVS1nt -1) in the NDUFS4 gene in Leigh syndrome". Human Genetics 112 (5-6): 563–6. doi:10.1007/s00439-002-0884-2. PMID 12616398. 
  • Scacco S, Petruzzella V, Budde S, Vergari R, Tamborra R, Panelli D et al. (Nov 2003). "Pathological mutations of the human NDUFS4 gene of the 18-kDa (AQDQ) subunit of complex I affect the expression of the protein and the assembly and function of the complex". The Journal of Biological Chemistry 278 (45): 44161–7. doi:10.1074/jbc.M307615200. PMID 12944388. 
  • Budde SM, van den Heuvel LP, Smeets RJ, Skladal D, Mayr JA, Boelen C et al. (2004). "Clinical heterogeneity in patients with mutations in the NDUFS4 gene of mitochondrial complex I". Journal of Inherited Metabolic Disease 26 (8): 813–5. doi:10.1023/B:BOLI.0000010003.14113.af. PMID 14765537. 
  • Papa S, Petruzzella V, Scacco S, Vergari R, Panelli D, Tamborra R et al. (Mar 2004). "Respiratory complex I in brain development and genetic disease". Neurochemical Research 29 (3): 547–60. doi:10.1023/B:NERE.0000014825.42365.16. PMID 15038602. 
  • Petruzzella V, Panelli D, Torraco A, Stella A, Papa S (Jul 2005). "Mutations in the NDUFS4 gene of mitochondrial complex I alter stability of the splice variants". FEBS Letters 579 (17): 3770–6. doi:10.1016/j.febslet.2005.05.035. PMID 15975579. 
  • Tao WA, Wollscheid B, O'Brien R, Eng JK, Li XJ, Bodenmiller B et al. (Aug 2005). "Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry". Nature Methods 2 (8): 591–8. doi:10.1038/nmeth776. PMID 16094384.