NDUFS3

NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase)
Identifiers
Symbols	NDUFS3 ; CI-30
External IDs	OMIM: 603846 MGI: 1915599 HomoloGene: 3346 GeneCards: NDUFS3 Gene
EC number	1.6.5.3, 1.6.99.3
Gene ontology Molecular function • NADH dehydrogenase activity • protein binding • NADH dehydrogenase (ubiquinone) activity • electron carrier activity Cellular component • nucleus • mitochondrion • mitochondrial inner membrane • mitochondrial respiratory chain complex I • mitochondrial membrane • myelin sheath Biological process • mitochondrial electron transport, NADH to ubiquinone • substantia nigra development • respiratory electron transport chain • negative regulation of cell growth • cellular metabolic process • small molecule metabolic process • reactive oxygen species metabolic process • negative regulation of intrinsic apoptotic signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4722	68349
Ensembl	ENSG00000213619	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	Chr 2: 90.89 – 90.9 Mb
PubMed search

NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial is an enzyme that in humans is encoded by the NDUFS3 gene on chromosome 11.^[1][2] 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.^[2]

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.^[3]

Function

This gene encodes one of the iron-sulfur protein (IP) components of complex I.^[2] The 45-subunit NADH:ubiquinone oxidoreductase (complex I) is the first enzyme complex in the electron transport chain of mitochondria.^[2][4] 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.^[4][5] It initiates the assembly of complex I in the mitochondrial matrix.^[3]

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. ^[6]

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.^[7][8] 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.^[9] However, the majority of cases are caused by mutations in nuclear-encoded genes.^[10][11] 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.^[12]

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.^[4]

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[13]
Radiography	Normal
Body temperature	Normal
Eye morphology	Normal
Clinical chemistry	Abnormal[14]
Haematology	Abnormal[15]
Peripheral blood lymphocytes	Normal
Micronucleus test	Normal
Heart weight	Abnormal[16]
Skin Histopathology	Normal
Brain histopathology	Normal
Salmonella infection	Normal[17]
Citrobacter infection	Normal[18]
All tests and analysis from[19][20]

Model organisms have been used in the study of NDUFS3 function. A conditional knockout mouse line, called Ndufs3^{tm1a(EUCOMM)Wtsi[21][22]} 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.^[23][24][25]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.^[19][26] Twenty five tests were carried out on mutant mice and six significant abnormalities were observed.^[19] 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.^[19]

See also

• NDUFS1

References

1. 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.
2. "Entrez Gene: NDUFS3 NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase)".
3. 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.
4. 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. PMID 21867691.
5. 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.
6. 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. PMID 20536557.
7. 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.
8. 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.
9. 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". Journal of Medical Genetics 49 (4): 277–83. doi:10.1136/jmedgenet-2012-100846. PMID 22499348.
10. 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.
11. 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.
12. 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. doi:10.1016/s0005-2728(98)00033-4. PMID 9593934.
13. "DEXA data for Ndufs3". Wellcome Trust Sanger Institute.
14. "Clinical chemistry data for Ndufs3". Wellcome Trust Sanger Institute.
15. "Haematology data for Ndufs3". Wellcome Trust Sanger Institute.
16. "Heart weight data for Ndufs3". Wellcome Trust Sanger Institute.
17. "Salmonella infection data for Ndufs3". Wellcome Trust Sanger Institute.
18. "Citrobacter infection data for Ndufs3". Wellcome Trust Sanger Institute.
19. 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.
20. Mouse Resources Portal, Wellcome Trust Sanger Institute.
21. "International Knockout Mouse Consortium".
22. "Mouse Genome Informatics".
23. 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.
24. Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
25. 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.
26. 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. 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.
• 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". Journal of Neural Transmission. Supplementum (61): 109–16. doi:10.1007/978-3-7091-6262-0_9. 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.