NDUFS4

NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial (NDUFS4) also known as NADH-ubiquinone oxidoreductase 18 kDa subunit is an enzyme that in humans is encoded by the NDUFS4 gene.[5][6] This gene encodes an nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, or NADH:ubiquinone oxidoreductase). Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome.[7]

NDUFS4
Identifiers
Aliases	NDUFS4, AQDQ, CI-18, CI-18 kDa, CI-AQDQ, NADH:ubiquinone oxidoreductase subunit S4, MC1DN1
External IDs	OMIM: 602694 MGI: 1343135 HomoloGene: 1866 GeneCards: NDUFS4
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q11.2 Start 53,560,633 bp[1] End 53,683,338 bp[1]
Gene location (Mouse) Chr. Chromosome 13 (mouse)[2] Band 13|13 D2.2 Start 114,287,795 bp[2] End 114,388,258 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • oxidoreductase activity, acting on NAD(P)H • NADH dehydrogenase (ubiquinone) activity Cellular component • membrane • respiratory chain complex I • mitochondrion • mitochondrial inner membrane • electron transport • mitochondrial respiratory chain complex I Biological process • regulation of protein phosphorylation • positive regulation of fibroblast proliferation • reactive oxygen species metabolic process • mitochondrial respiratory chain complex I assembly • brain development • cellular respiration • response to cAMP • oxidation-reduction process • cAMP-mediated signaling • electron transport chain • mitochondrial electron transport, NADH to ubiquinone Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4724	17993
Ensembl	ENSG00000164258	ENSMUSG00000021764
UniProt	O43181	Q9CXZ1
RefSeq (mRNA)	NM_002495 NM_001318051	NM_010887
RefSeq (protein)	NP_001304980 NP_002486	NP_035017
Location (UCSC)	Chr 5: 53.56 – 53.68 Mb	Chr 13: 114.29 – 114.39 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

NDUFS4 is located on the q arm of chromosome 5 in position 11.2 and has 8 exons.[8] The NDUFS4 gene produces a 20.1 kDa protein composed of 175 amino acids.[9][10] NDUFS4, the protein encoded by this gene, is a member of the complex I NDUFS4 subunit family. It is a peripheral membrane protein located on the matrix side of the inner mitochondrial membrane. NDUFS4 is a component of the iron-sulfur (IP) fragment of the enzyme and contains a transit peptide domain, 4 turns, 6 beta strands, and 4 alpha helixes.[11][12] Alternative splicing results in multiple transcript variants.[7]

Function

Complex I, or NADH:ubiquinone oxidoreductase, the first multisubunit enzyme complex of the mitochondrial respiratory 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.[5][7]

Clinical significance

Mutations in the NDUFS4 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.[13][14] 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.[15] However, the majority of cases are caused by mutations in nuclear-encoded genes.[16][17] 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.[18] 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.

Interactions

NDUFS4 has been shown to have 58 binary protein-protein interactions including 57 co-complex interactions. NDUFS4 appears to interact with UBE2G2.[19]

References

1. GRCh38: Ensembl release 89: ENSG00000164258 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000021764 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. van den Heuvel L, Ruitenbeek W, Smeets R, Gelman-Kohan Z, Elpeleg O, Loeffen J, Trijbels F, Mariman E, de Bruijn D, Smeitink J (February 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.
6. 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.
7. "Entrez Gene: NDUFS4 NADH dehydrogenase (ubiquinone) Fe-S protein 4, 18kDa (NADH-coenzyme Q reductase)". This article incorporates text from this source, which is in the public domain.
8. "Entrez Gene: Cytochrome c oxidase assembly factor 7 (putative)". Retrieved 2018-08-08. This article incorporates text from this source, which is in the public domain.
9. Yao, Daniel. "Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information". amino.heartproteome.org. Retrieved 2018-08-28.
10. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
11. "NDUFS4 - NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial precursor - Homo sapiens (Human) - NDUFS4 gene & protein". www.uniprot.org. Retrieved 2018-08-28. This article incorporates text available under the CC BY 4.0 license.
12. "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
13. Kirby DM, Salemi R, Sugiana C, Ohtake A, Parry L, Bell KM, Kirk EP, Boneh A, Taylor RW, Dahl HH, Ryan MT, Thorburn DR (September 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. PMC 516258. PMID 15372108.
14. McFarland R, Kirby DM, Fowler KJ, Ohtake A, Ryan MT, Amor DJ, Fletcher JM, Dixon JW, Collins FA, Turnbull DM, Taylor RW, Thorburn DR (January 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.
15. Haack TB, Haberberger B, Frisch EM, Wieland T, Iuso A, Gorza M, Strecker V, Graf E, Mayr JA, Herberg U, Hennermann JB, Klopstock T, Kuhn KA, Ahting U, Sperl W, Wilichowski E, Hoffmann GF, Tesarova M, Hansikova H, Zeman J, Plecko B, Zeviani M, Wittig I, Strom TM, Schuelke M, Freisinger P, Meitinger T, Prokisch H (April 2012). "Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing" (PDF). Journal of Medical Genetics. 49 (4): 277–83. doi:10.1136/jmedgenet-2012-100846. PMID 22499348.
16. Loeffen JL, Smeitink JA, Trijbels JM, Janssen AJ, Triepels RH, Sengers RC, van den Heuvel LP (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.
17. Triepels RH, Van Den Heuvel LP, Trijbels JM, Smeitink JA (2001). "Respiratory chain complex I deficiency". American Journal of Medical Genetics. 106 (1): 37–45. doi:10.1002/ajmg.1397. PMID 11579423.
18. 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 (BBA) - Bioenergetics. 1364 (2): 271–86. doi:10.1016/s0005-2728(98)00033-4. PMID 9593934.
19. "58 binary interactions found for search term NDUFS4". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-08-28.

Further reading

• Leshinsky-Silver E, Lebre AS, Minai L, Saada A, Steffann J, Cohen S, Rötig A, Munnich A, Lev D, Lerman-Sagie T (July 2009). "NDUFS4 mutations cause Leigh syndrome with predominant brainstem involvement". Molecular Genetics and Metabolism. 97 (3): 185–9. doi:10.1016/j.ymgme.2009.03.002. PMID 19364667.
• Papa S, Sardanelli AM, Scacco S, Petruzzella V, Technikova-Dobrova Z, Vergari R, Signorile A (February 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 (February 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, Trijbels JM, Smeitink JA (December 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, Capaldi RA (March 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, van den Heuvel L, Smeitink J (February 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, Papa S (March 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 (April 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 (June 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 (September 2002). "The NDUFS4 nuclear gene of complex I of mitochondria and the cAMP cascade". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 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, Goldenberg A, Dumez Y, Dommergues M, Rustin P, Munnich A, Rötig A (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, van den Heuvel LP, Smeitink JA, Papa S (November 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, Petruzzella V, Papa S, Smeitink JA (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, Corsi P, Picciariello M, Lambo R, Bertini E, Santorelli FM (March 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 (July 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, Watts JD, Hood L, Aebersold R (August 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.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.