NDUFS3

NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial is an enzyme that in humans is encoded by the NDUFS3 gene on chromosome 11.[4][5] This gene encodes one of the iron-sulfur protein (IP) components of mitochondrial NADH:ubiquinone oxidoreductase (complex I). Mutations in this gene are associated with Leigh syndrome resulting from mitochondrial complex I deficiency.[5]

NDUFS3
Identifiers
Aliases	NDUFS3, CI-30, NADH:ubiquinone oxidoreductase core subunit S3, MC1DN8
External IDs	OMIM: 603846 MGI: 1915599 HomoloGene: 3346 GeneCards: NDUFS3
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11p11.2 Start 47,565,336 bp[1] End 47,584,562 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • oxidoreductase activity, acting on NAD(P)H • GO:0001948 protein binding • electron transfer activity • oxidoreductase activity • NADH dehydrogenase activity • NADH dehydrogenase (ubiquinone) activity Cellular component • membrane • mitochondrial membranes • myelin • mitochondrial respiratory chain complex I • mitochondrial matrix • mitochondrion • mitochondrial inner membrane • electron transport • nuclear body Biological process • substantia nigra development • negative regulation of intrinsic apoptotic signaling pathway • reactive oxygen species metabolic process • mitochondrial respiratory chain complex I assembly • negative regulation of cell growth • oxidation-reduction process • mitochondrial electron transport, NADH to ubiquinone • cellular respiration Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4722	68349
Ensembl	ENSG00000213619 ENSG00000285387	ENSMUSG00000005510
UniProt	O75489	Q9DCT2
RefSeq (mRNA)	NM_004551	NM_026688
RefSeq (protein)	NP_004542	NP_080964
Location (UCSC)	Chr 11: 47.57 – 47.58 Mb	n/a
PubMed search	[2]	[3]
Wikidata
View/Edit Human View/Edit Mouse

Structure

The NDUFS3 gene encodes a protein subunit consisting of 263 amino acids. This protein is synthesized in the cytoplasm and then transported to the mitochondria via a signal peptide. Two mutations that occur in its highly conserved C-terminal region, T145I and R199W, are causally linked to Leigh syndrome and optic atrophy. Nonetheless, despite its crucial biological role, the human NDUFS3 remains structurally poorly understood.[6]

Function

This gene encodes one of the iron-sulfur protein (IP) components of complex I.[5] The 45-subunit NADH:ubiquinone oxidoreductase (complex I) is the first enzyme complex in the electron transport chain of mitochondria.[5][7] As a catalytic subunit, NDUFS3 plays a vital role in the proper assembly of complex I and is recruited to the inner mitochondrial membrane to form an early assembly intermediate with NDUFS2.[7][8] It initiates the assembly of complex I in the mitochondrial matrix.[6]

Cleavage of NDUFS3 by GzmA has been observed to activate a programmed cell death pathway which results in mitochondrial dysfunction and reactive oxygen species (ROS) generation. [9]

Clinical significance

Mutations in the NDUFS3 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.[10][11] 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.[12] However, the majority of cases are caused by mutations in nuclear-encoded genes.[13][14] 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.[15]

NDUFS3 has also been implicated in breast cancer and ductal carcinoma and, thus, may serve as a novel biomarker for tracking cancer progression and invasiveness.[7]

Model organisms

Ndufs3 knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Abnormal
Recessive lethal study	Abnormal
Fertility	Normal
Body weight	Normal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Abnormal[16]
Radiography	Normal
Body temperature	Normal
Eye morphology	Normal
Clinical chemistry	Abnormal[17]
Haematology	Abnormal[18]
Peripheral blood lymphocytes	Normal
Micronucleus test	Normal
Heart weight	Abnormal[19]
Skin Histopathology	Normal
Brain histopathology	Normal
Salmonella infection	Normal[20]
Citrobacter infection	Normal[21]
All tests and analysis from[22][23]

Model organisms have been used in the study of NDUFS3 function. A conditional knockout mouse line, called Ndufs3^{tm1a(EUCOMM)Wtsi}[24][25] was generated as part of the International Knockout Mouse Consortium program—a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[26][27][28]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[22][29] Twenty five tests were carried out on mutant mice and six significant abnormalities were observed.[22] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; males had an increased lean body mass and heart weight, and a decrease in some plasma chemistry and haematology parameters.[22]

See also

• NDUFS1

References

1. ENSG00000285387 GRCh38: Ensembl release 89: ENSG00000213619, ENSG00000285387 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. 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. S2CID 46818955.
5. "Entrez Gene: NDUFS3 NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase)".
6. Jaokar, TM; Patil, DP; Shouche, YS; Gaikwad, SM; Suresh, CG (December 2013). "Human mitochondrial NDUFS3 protein bearing Leigh syndrome mutation is more prone to aggregation than its wild-type". Biochimie. 95 (12): 2392–403. doi:10.1016/j.biochi.2013.08.032. PMID 24028823.
7. Suhane S, Berel D, Ramanujan VK (Sep 2011). "Biomarker signatures of mitochondrial NDUFS3 in invasive breast carcinoma". Biochemical and Biophysical Research Communications. 412 (4): 590–5. doi:10.1016/j.bbrc.2011.08.003. PMC 3171595. PMID 21867691.
8. Saada A, Vogel RO, Hoefs SJ, van den Brand MA, Wessels HJ, Willems PH, Venselaar H, Shaag A, Barghuti F, Reish O, Shohat M, Huynen MA, Smeitink JA, van den Heuvel LP, Nijtmans LG (Jun 2009). "Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease". American Journal of Human Genetics. 84 (6): 718–27. doi:10.1016/j.ajhg.2009.04.020. PMC 2694978. PMID 19463981.
9. Lieberman J (May 2010). "Granzyme A activates another way to die". Immunological Reviews. 235 (1): 93–104. doi:10.1111/j.0105-2896.2010.00902.x. PMC 2905780. PMID 20536557.
10. Kirby DM, Salemi R, Sugiana C, Ohtake A, Parry L, Bell KM, Kirk EP, Boneh A, Taylor RW, Dahl HH, Ryan MT, Thorburn DR (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. PMC 516258. PMID 15372108.
11. McFarland R, Kirby DM, Fowler KJ, Ohtake A, Ryan MT, Amor DJ, Fletcher JM, Dixon JW, Collins FA, Turnbull DM, Taylor RW, Thorburn DR (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. S2CID 21076359.
12. 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 (Apr 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. S2CID 3177674.
13. 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.
14. 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.
15. 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.
16. "DEXA data for Ndufs3". Wellcome Trust Sanger Institute.
17. "Clinical chemistry data for Ndufs3". Wellcome Trust Sanger Institute.
18. "Haematology data for Ndufs3". Wellcome Trust Sanger Institute.
19. "Heart weight data for Ndufs3". Wellcome Trust Sanger Institute.
20. "Salmonella infection data for Ndufs3". Wellcome Trust Sanger Institute.
21. "Citrobacter infection data for Ndufs3". Wellcome Trust Sanger Institute.
22. Gerdin, AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x. S2CID 85911512.
23. Mouse Resources Portal, Wellcome Trust Sanger Institute.
24. "International Knockout Mouse Consortium".
25. "Mouse Genome Informatics".
26. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
27. Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
28. Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. S2CID 18872015.
29. van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.

Further reading

• Dawson SJ, White LA (May 1992). "Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin". The Journal of Infection. 24 (3): 317–20. doi:10.1016/S0163-4453(05)80037-4. PMID 1602151.
• Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Loeffen J, van den Heuvel L, Smeets R, Triepels R, Sengers R, Trijbels F, Smeitink J (Jun 1998). "cDNA sequence and chromosomal localization of the remaining three human nuclear encoded iron sulphur protein (IP) subunits of complex I: the human IP fraction is completed". Biochemical and Biophysical Research Communications. 247 (3): 751–8. doi:10.1006/bbrc.1998.8882. PMID 9647766.
• Loeffen JL, Triepels RH, van den Heuvel LP, Schuelke M, Buskens CA, Smeets RJ, Trijbels JM, Smeitink JA (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.
• Hu RM, Han ZG, Song HD, Peng YD, Huang QH, Ren SX, Gu YJ, Huang CH, Li YB, Jiang CL, Fu G, Zhang QH, Gu BW, Dai M, Mao YF, Gao GF, Rong R, Ye M, Zhou J, Xu SH, Gu J, Shi JX, Jin WR, Zhang CK, Wu TM, Huang GY, Chen Z, Chen MD, Chen JL (Aug 2000). "Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning". Proceedings of the National Academy of Sciences of the United States of America. 97 (17): 9543–8. Bibcode:2000PNAS...97.9543H. doi:10.1073/pnas.160270997. PMC 16901. PMID 10931946.
• Procaccio V, Lescuyer P, Bourges I, Beugnot R, Duborjal H, Depetris D, Mousson B, Montfort MF, Smeets H, De Coo R, Issartel JP (Sep 2000). "Human NDUFS3 gene coding for the 30-kDa subunit of mitochondrial complex I: genomic organization and expression". Mammalian Genome. 11 (9): 808–10. doi:10.1007/s003350010160. PMID 10967146. S2CID 6619646.
• Triepels RH, Hanson BJ, van den Heuvel LP, Sundell L, Marusich MF, Smeitink JA, Capaldi RA (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.
• Kim SH, Fountoulakis M, Dierssen M, Lubec G (2002). "Decreased protein levels of complex I 30-kDa subunit in fetal Down syndrome brains". Protein Expression in Down Syndrome Brain. Journal of Neural Transmission. Supplementum. pp. 109–16. doi:10.1007/978-3-7091-6262-0_9. ISBN 978-3-211-83704-7. PMID 11771736.
• Bénit P, Slama A, Cartault F, Giurgea I, Chretien D, Lebon S, Marsac C, Munnich A, Rötig A, Rustin P (Jan 2004). "Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome". Journal of Medical Genetics. 41 (1): 14–7. doi:10.1136/jmg.2003.014316. PMC 1757256. PMID 14729820.
• Bourges I, Ramus C, Mousson de Camaret B, Beugnot R, Remacle C, Cardol P, Hofhaus G, Issartel JP (Nov 2004). "Structural organization of mitochondrial human complex I: role of the ND4 and ND5 mitochondria-encoded subunits and interaction with prohibitin". The Biochemical Journal. 383 (Pt. 3): 491–9. doi:10.1042/BJ20040256. PMC 1133742. PMID 15250827.
• Huang G, Chen Y, Lu H, Cao X (Feb 2007). "Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-beta and retinoic acid-induced cancer cell death". Cell Death and Differentiation. 14 (2): 327–37. doi:10.1038/sj.cdd.4402004. PMID 16826196.
• Vogel RO, Dieteren CE, van den Heuvel LP, Willems PH, Smeitink JA, Koopman WJ, Nijtmans LG (Mar 2007). "Identification of mitochondrial complex I assembly intermediates by tracing tagged NDUFS3 demonstrates the entry point of mitochondrial subunits". The Journal of Biological Chemistry. 282 (10): 7582–90. doi:10.1074/jbc.M609410200. PMID 17209039.