NDUFS3: Difference between revisions

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{{Infobox_gene}}
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'''NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial''' is an [[enzyme]] that in humans is encoded by the ''NDUFS3'' [[gene]] on chromosome 11.<ref name="pmid9763677">{{cite journal | vauthors = Emahazion T, Beskow A, Gyllensten U, Brookes AJ | title = Intron based radiation hybrid mapping of 15 complex I genes of the human electron transport chain | journal = Cytogenetics and Cell Genetics | volume = 82 | issue = 1–2 | pages = 115–9 | date = Nov 1998 | pmid = 9763677 | pmc = | doi = 10.1159/000015082 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: NDUFS3 NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4722| accessdate = }}</ref> This gene encodes one of the iron-sulfur protein (IP) components of [[mitochondria]]l [[NADH:ubiquinone reductase (H+-translocating)|NADH:ubiquinone oxidoreductase]] (complex I). Mutations in this gene are associated with [[Leigh syndrome]] resulting from mitochondrial complex I deficiency.<ref name="entrez"/>
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| update_protein_box = yes
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Structure ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =  
| Name = NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase)
| HGNCid = 7710
| Symbol = NDUFS3
| AltSymbols =;
| OMIM = 603846
| ECnumber = 
| Homologene = 3346
| MGIid = 1915599
| GeneAtlas_image1 = PBB_GE_NDUFS3_201740_at_tn.png
| Function = {{GNF_GO|id=GO:0003954 |text = NADH dehydrogenase activity}} {{GNF_GO|id=GO:0008137 |text = NADH dehydrogenase (ubiquinone) activity}}
| Component = {{GNF_GO|id=GO:0005624 |text = membrane fraction}} {{GNF_GO|id=GO:0005739 |text = mitochondrion}}
| Process = {{GNF_GO|id=GO:0006120 |text = mitochondrial electron transport, NADH to ubiquinone}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 4722
    | Hs_Ensembl = ENSG00000110536
    | Hs_RefseqProtein = NP_004542
    | Hs_RefseqmRNA = NM_004551
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 11
    | Hs_GenLoc_start = 47543464
    | Hs_GenLoc_end = 47562690
    | Hs_Uniprot = Q8WUK0
    | Mm_EntrezGene = 68349
    | Mm_Ensembl = ENSMUSG00000005510
    | Mm_RefseqmRNA = NM_026688
    | Mm_RefseqProtein = NP_080964
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 2
    | Mm_GenLoc_start = 90695475
    | Mm_GenLoc_end = 90705560
    | Mm_Uniprot = Q8BTZ3
  }}
}}
'''NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase)''', also known as '''NDUFS3''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: NDUFS3 NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4722| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
The ''NDUFS3'' gene encodes a protein subunit consisting of 263 [[amino acid]]s. This protein is synthesized in the [[cytoplasm]] and then transported to the [[mitochondria]] via a [[targeting sequence|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.<ref name=pmid24028823>{{cite journal|last1=Jaokar|first1=TM|last2=Patil|first2=DP|last3=Shouche|first3=YS|last4=Gaikwad|first4=SM|last5=Suresh|first5=CG|title=Human mitochondrial NDUFS3 protein bearing Leigh syndrome mutation is more prone to aggregation than its wild-type.|journal=Biochimie|date=December 2013|volume=95|issue=12|pages=2392–403|pmid=24028823|doi=10.1016/j.biochi.2013.08.032}}</ref>
{{PBB_Summary
| section_title =
| summary_text = The multisubunit NADH:ubiquinone oxidoreductase (complex I) is the first enzyme complex in the electron transport chain of mitochondria. The iron-sulfur protein (IP) fraction of complex I is made up of 7 subunits. See NDUFS1 (MIM 157655).[supplied by OMIM]<ref name="entrez">{{cite web | title = Entrez Gene: NDUFS3 NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4722| accessdate = }}</ref>
}}


==References==
== Function ==
{{reflist|2}}
 
==Further reading==
This gene encodes one of the [[iron-sulfur protein]] (IP) components of complex I.<ref name="entrez"/> The 45-subunit [[Electron transport chain#Complex I|NADH:ubiquinone oxidoreductase]] (complex I) is the first enzyme complex in the [[electron transport chain]] of [[mitochondrion|mitochondria]].<ref name="entrez"/><ref name=pmid21867691>{{cite journal | vauthors = Suhane S, Berel D, Ramanujan VK | title = Biomarker signatures of mitochondrial NDUFS3 in invasive breast carcinoma | journal = Biochemical and Biophysical Research Communications | volume = 412 | issue = 4 | pages = 590–5 | date = Sep 2011 | pmid = 21867691 | doi = 10.1016/j.bbrc.2011.08.003 | pmc=3171595}}</ref> 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]].<ref name=pmid21867691/><ref>{{cite journal | vauthors = 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 | title = Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease | journal = American Journal of Human Genetics | volume = 84 | issue = 6 | pages = 718–27 | date = Jun 2009 | pmid = 19463981 | doi = 10.1016/j.ajhg.2009.04.020 | pmc=2694978}}</ref> It initiates the assembly of complex I in the [[mitochondrial matrix]].<ref name=pmid24028823/>
{{refbegin | 2}}
 
{{PBB_Further_reading
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.
| citations =  
<ref>{{cite journal | vauthors = Lieberman J | title = Granzyme A activates another way to die | journal = Immunological Reviews | volume = 235 | issue = 1 | pages = 93–104 | date = May 2010 | pmid = 20536557 | doi = 10.1111/j.0105-2896.2010.00902.x | pmc=2905780}}</ref>
*{{cite journal | author=Dawson SJ, White LA |title=Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin. |journal=J. Infect. |volume=24 |issue= 3 |pages= 317-20 |year= 1992 |pmid= 1602151 |doi= }}
 
*{{cite journal  | author=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1-2 |pages= 171-4 |year= 1994 |pmid= 8125298 |doi= }}
== Clinical significance ==
*{{cite journal  | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, ''et al.'' |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149-56 |year= 1997 |pmid= 9373149 |doi= }}
 
*{{cite journal  | author=Loeffen J, van den Heuvel L, Smeets R, ''et al.'' |title=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. |journal=Biochem. Biophys. Res. Commun. |volume=247 |issue= 3 |pages= 751-8 |year= 1998 |pmid= 9647766 |doi= 10.1006/bbrc.1998.8882 }}
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.<ref>{{cite journal | vauthors = Kirby DM, Salemi R, Sugiana C, Ohtake A, Parry L, Bell KM, Kirk EP, Boneh A, Taylor RW, Dahl HH, Ryan MT, Thorburn DR | title = NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency | journal = The Journal of Clinical Investigation | volume = 114 | issue = 6 | pages = 837–45 | date = Sep 2004 | pmid = 15372108 | doi = 10.1172/JCI20683 | pmc=516258}}</ref><ref>{{cite journal | vauthors = McFarland R, Kirby DM, Fowler KJ, Ohtake A, Ryan MT, Amor DJ, Fletcher JM, Dixon JW, Collins FA, Turnbull DM, Taylor RW, Thorburn DR | title = De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency | journal = Annals of Neurology | volume = 55 | issue = 1 | pages = 58–64 | date = Jan 2004 | pmid = 14705112 | doi = 10.1002/ana.10787 }}</ref> 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.<ref>{{cite journal | vauthors = 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 | title = Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing | journal = Journal of Medical Genetics | volume = 49 | issue = 4 | pages = 277–83 | date = Apr 2012 | pmid = 22499348 | doi = 10.1136/jmedgenet-2012-100846 }}</ref> However, the majority of cases are caused by mutations in nuclear-encoded genes.<ref>{{cite journal | vauthors = Loeffen JL, Smeitink JA, Trijbels JM, Janssen AJ, Triepels RH, Sengers RC, van den Heuvel LP | title = Isolated complex I deficiency in children: clinical, biochemical and genetic aspects | journal = Human Mutation | volume = 15 | issue = 2 | pages = 123–34 | date = 2000 | pmid = 10649489 | doi = 10.1002/(SICI)1098-1004(200002)15:2<123::AID-HUMU1>3.0.CO;2-P }}</ref><ref>{{cite journal | vauthors = Triepels RH, Van Den Heuvel LP, Trijbels JM, Smeitink JA | title = Respiratory chain complex I deficiency | journal = American Journal of Medical Genetics | volume = 106 | issue = 1 | pages = 37–45 | date = 2001 | pmid = 11579423 | doi = 10.1002/ajmg.1397 }}</ref> 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.<ref>{{cite journal | vauthors = Robinson BH | title = Human complex I deficiency: clinical spectrum and involvement of oxygen free radicals in the pathogenicity of the defect | journal = Biochimica et Biophysica Acta | volume = 1364 | issue = 2 | pages = 271–86 | date = May 1998 | pmid = 9593934 | doi=10.1016/s0005-2728(98)00033-4}}</ref>
*{{cite journal | author=Emahazion T, Beskow A, Gyllensten U, Brookes AJ |title=Intron based radiation hybrid mapping of 15 complex I genes of the human electron transport chain. |journal=Cytogenet. Cell Genet. |volume=82 |issue= 1-2 |pages= 115-9 |year= 1998 |pmid= 9763677 |doi= }}
 
*{{cite journal  | author=Loeffen JL, Triepels RH, van den Heuvel LP, ''et al.'' |title=cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase: human complex I cDNA characterization completed. |journal=Biochem. Biophys. Res. Commun. |volume=253 |issue= 2 |pages= 415-22 |year= 1999 |pmid= 9878551 |doi= 10.1006/bbrc.1998.9786 }}
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.<ref name=pmid21867691/>
*{{cite journal | author=Hu RM, Han ZG, Song HD, ''et al.'' |title=Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue= 17 |pages= 9543-8 |year= 2000 |pmid= 10931946 |doi= 10.1073/pnas.160270997 }}
 
*{{cite journal | author=Procaccio V, Lescuyer P, Bourges I, ''et al.'' |title=Human NDUFS3 gene coding for the 30-kDa subunit of mitochondrial complex I: genomic organization and expression. |journal=Mamm. Genome |volume=11 |issue= 9 |pages= 808-10 |year= 2000 |pmid= 10967146 |doi= }}
== Model organisms ==
*{{cite journal | author=Triepels RH, Hanson BJ, van den Heuvel LP, ''et al.'' |title=Human complex I defects can be resolved by monoclonal antibody analysis into distinct subunit assembly patterns. |journal=J. Biol. Chem. |volume=276 |issue= 12 |pages= 8892-7 |year= 2001 |pmid= 11112787 |doi= 10.1074/jbc.M009903200 }}
{| class="wikitable sortable collapsible collapsed" border="1" cellpadding="2" style="float: right;" |
*{{cite journal  | author=Kim SH, Fountoulakis M, Dierssen M, Lubec G |title=Decreased protein levels of complex I 30-kDa subunit in fetal Down syndrome brains. |journal=J. Neural Transm. Suppl. |volume= |issue= 61 |pages= 109-16 |year= 2002 |pmid= 11771736 |doi=  }}
|+ ''Ndufs3'' knockout mouse phenotype
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
|-
*{{cite journal  | author=Bénit P, Slama A, Cartault F, ''et al.'' |title=Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome. |journal=J. Med. Genet. |volume=41 |issue= 1 |pages= 14-7 |year= 2004 |pmid= 14729820 |doi=  }}
! Characteristic!! Phenotype
*{{cite journal  | author=Bourges I, Ramus C, Mousson de Camaret B, ''et al.'' |title=Structural organization of mitochondrial human complex I: role of the ND4 and ND5 mitochondria-encoded subunits and interaction with prohibitin. |journal=Biochem. J. |volume=383 |issue= Pt. 3 |pages= 491-9 |year= 2005 |pmid= 15250827 |doi= 10.1042/BJ20040256 }}
 
*{{cite journal  | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
|-
*{{cite journal  | author=Huang G, Chen Y, Lu H, Cao X |title=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. |journal=Cell Death Differ. |volume=14 |issue= 2 |pages= 327-37 |year= 2007 |pmid= 16826196 |doi= 10.1038/sj.cdd.4402004 }}
| [[Homozygote]] viability || bgcolor="#C40000"|Abnormal
*{{cite journal  | author=Vogel RO, Dieteren CE, van den Heuvel LP, ''et al.'' |title=Identification of mitochondrial complex I assembly intermediates by tracing tagged NDUFS3 demonstrates the entry point of mitochondrial subunits. |journal=J. Biol. Chem. |volume=282 |issue= 10 |pages= 7582-90 |year= 2007 |pmid= 17209039 |doi= 10.1074/jbc.M609410200 }}
|-
}}
| [[Recessive]] lethal study || bgcolor="#C40000"|Abnormal
|-
| Fertility || bgcolor="#488ED3"|Normal
|-
| Body weight || bgcolor="#488ED3"|Normal
|-
| [[Open Field (animal test)|Anxiety]] || bgcolor="#488ED3"|Normal
|-
| Neurological assessment || bgcolor="#488ED3"|Normal
|-
| Grip strength || bgcolor="#488ED3"|Normal
|-
| [[Hot plate test|Hot plate]] || bgcolor="#488ED3"|Normal
|-
| [[Dysmorphology]] || bgcolor="#488ED3"|Normal
|-
| [[Indirect calorimetry]] || bgcolor="#488ED3"|Normal
|-
| [[Glucose tolerance test]] || bgcolor="#488ED3"|Normal
|-
| [[Auditory brainstem response]] || bgcolor="#488ED3"|Normal
|-
| [[Dual-energy X-ray absorptiometry|DEXA]] || bgcolor="#C40000"|Abnormal<ref name="DEXA">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MASA/body-composition-dexa/ |title=DEXA data for Ndufs3 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| [[Radiography]] || bgcolor="#488ED3"|Normal
|-
| Body temperature || bgcolor="#488ED3"|Normal
|-
| Eye morphology || bgcolor="#488ED3"|Normal
|-
| [[Clinical chemistry]] || bgcolor="#C40000"|Abnormal<ref name="Clinical chemistry">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MASA/plasma-chemistry/ |title=Clinical chemistry data for Ndufs3 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| [[Haematology]] || bgcolor="#C40000"|Abnormal<ref name="Haematology">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MASA/haematology-cbc/ |title=Haematology data for Ndufs3 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| [[Peripheral blood lymphocyte]]s || bgcolor="#488ED3"|Normal
|-
| [[Micronucleus test]] || bgcolor="#488ED3"|Normal
|-
| Heart weight || bgcolor="#C40000"|Abnormal<ref name="Heart weight">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MASA/heart-weight/ |title=Heart weight data for Ndufs3 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| Skin Histopathology || bgcolor="#488ED3"|Normal
|-
| Brain histopathology || bgcolor="#488ED3"|Normal
|-
| ''[[Salmonella]]'' infection || bgcolor="#488ED3"|Normal<ref name="''Salmonella'' infection">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MASA/salmonella-challenge/ |title=''Salmonella'' infection data for Ndufs3 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| ''[[Citrobacter]]'' infection || bgcolor="#488ED3"|Normal<ref name="''Citrobacter'' infection">{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MASA/citrobacter-challenge/ |title=''Citrobacter'' infection data for Ndufs3 |publisher=Wellcome Trust Sanger Institute}}</ref>
|-
| colspan=2; style="text-align: center;" | All tests and analysis from<ref name="mgp_reference">{{cite journal | doi = 10.1111/j.1755-3768.2010.4142.x | title = The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice | year = 2010 | last1 = Gerdin | first1 = AK | journal = Acta Ophthalmologica | volume = 88 | pages =  925–7 }}</ref><ref>[http://www.sanger.ac.uk/mouseportal/ Mouse Resources Portal], Wellcome Trust Sanger Institute.</ref>
|}
[[Model organism]]s have been used in the study of NDUFS3 function. A conditional [[knockout mouse]] line, called ''Ndufs3<sup>tm1a(EUCOMM)Wtsi</sup>''<ref name="allele_ref">{{cite web |url=http://www.knockoutmouse.org/martsearch/search?query=Ndufs3 |title=International Knockout Mouse Consortium}}</ref><ref name="mgi_allele_ref">{{cite web |url=http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4433795 |title=Mouse Genome Informatics}}</ref> 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.<ref name="pmid21677750">{{cite journal | vauthors = 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 | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = Jun 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}</ref><ref name="mouse_library">{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = Jun 2011 | pmid = 21677718 | doi = 10.1038/474262a }}</ref><ref name="mouse_for_all_reasons">{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = Jan 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }}</ref>
 
Male and female animals underwent a standardized [[phenotypic screen]] to determine the effects of deletion.<ref name="mgp_reference" /><ref name="pmid21722353">{{cite journal | vauthors = van der Weyden L, White JK, Adams DJ, Logan DW | title = The mouse genetics toolkit: revealing function and mechanism | journal = Genome Biology | volume = 12 | issue = 6 | pages = 224 | year = 2011 | pmid = 21722353 | pmc = 3218837 | doi = 10.1186/gb-2011-12-6-224 }}</ref>
Twenty five tests were carried out on [[mutant]] mice and six significant abnormalities were observed.<ref name="mgp_reference" />  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.<ref name="mgp_reference" />
 
== See also ==
{{Portal|Mitochondria}}
*[[NDUFS1]]
 
== References ==
{{reflist|33em}}
 
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Dawson SJ, White LA | title = Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin | journal = The Journal of Infection | volume = 24 | issue = 3 | pages = 317–20 | date = May 1992 | pmid = 1602151 | doi = 10.1016/S0163-4453(05)80037-4 }}
* {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | date = Jan 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
* {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–56 | date = Oct 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
* {{cite journal | vauthors = Loeffen J, van den Heuvel L, Smeets R, Triepels R, Sengers R, Trijbels F, Smeitink J | title = 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 | journal = Biochemical and Biophysical Research Communications | volume = 247 | issue = 3 | pages = 751–8 | date = Jun 1998 | pmid = 9647766 | doi = 10.1006/bbrc.1998.8882 }}
* {{cite journal | vauthors = Loeffen JL, Triepels RH, van den Heuvel LP, Schuelke M, Buskens CA, Smeets RJ, Trijbels JM, Smeitink JA | title = cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase: human complex I cDNA characterization completed | journal = Biochemical and Biophysical Research Communications | volume = 253 | issue = 2 | pages = 415–22 | date = Dec 1998 | pmid = 9878551 | doi = 10.1006/bbrc.1998.9786 }}
* {{cite journal | vauthors = 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 | title = Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 17 | pages = 9543–8 | date = Aug 2000 | pmid = 10931946 | pmc = 16901 | doi = 10.1073/pnas.160270997 }}
* {{cite journal | vauthors = Procaccio V, Lescuyer P, Bourges I, Beugnot R, Duborjal H, Depetris D, Mousson B, Montfort MF, Smeets H, De Coo R, Issartel JP | title = Human NDUFS3 gene coding for the 30-kDa subunit of mitochondrial complex I: genomic organization and expression | journal = Mammalian Genome | volume = 11 | issue = 9 | pages = 808–10 | date = Sep 2000 | pmid = 10967146 | doi = 10.1007/s003350010160 }}
* {{cite journal | vauthors = Triepels RH, Hanson BJ, van den Heuvel LP, Sundell L, Marusich MF, Smeitink JA, Capaldi RA | title = Human complex I defects can be resolved by monoclonal antibody analysis into distinct subunit assembly patterns | journal = The Journal of Biological Chemistry | volume = 276 | issue = 12 | pages = 8892–7 | date = Mar 2001 | pmid = 11112787 | doi = 10.1074/jbc.M009903200 }}
* {{cite journal | vauthors = Kim SH, Fountoulakis M, Dierssen M, Lubec G | title = Decreased protein levels of complex I 30-kDa subunit in fetal Down syndrome brains | journal = Journal of Neural Transmission. Supplementum | volume =  | issue = 61 | pages = 109–16 | year = 2002 | pmid = 11771736 | doi = 10.1007/978-3-7091-6262-0_9 }}
* {{cite journal | vauthors = Bénit P, Slama A, Cartault F, Giurgea I, Chretien D, Lebon S, Marsac C, Munnich A, Rötig A, Rustin P | title = Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome | journal = Journal of Medical Genetics | volume = 41 | issue = 1 | pages = 14–7 | date = Jan 2004 | pmid = 14729820 | pmc = 1757256 | doi = 10.1136/jmg.2003.014316 }}
* {{cite journal | vauthors = Bourges I, Ramus C, Mousson de Camaret B, Beugnot R, Remacle C, Cardol P, Hofhaus G, Issartel JP | title = Structural organization of mitochondrial human complex I: role of the ND4 and ND5 mitochondria-encoded subunits and interaction with prohibitin | journal = The Biochemical Journal | volume = 383 | issue = Pt. 3 | pages = 491–9 | date = Nov 2004 | pmid = 15250827 | pmc = 1133742 | doi = 10.1042/BJ20040256 }}
* {{cite journal | vauthors = Huang G, Chen Y, Lu H, Cao X | title = 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 | journal = Cell Death and Differentiation | volume = 14 | issue = 2 | pages = 327–37 | date = Feb 2007 | pmid = 16826196 | doi = 10.1038/sj.cdd.4402004 }}
* {{cite journal | vauthors = Vogel RO, Dieteren CE, van den Heuvel LP, Willems PH, Smeitink JA, Koopman WJ, Nijtmans LG | title = Identification of mitochondrial complex I assembly intermediates by tracing tagged NDUFS3 demonstrates the entry point of mitochondrial subunits | journal = The Journal of Biological Chemistry | volume = 282 | issue = 10 | pages = 7582–90 | date = Mar 2007 | pmid = 17209039 | doi = 10.1074/jbc.M609410200 }}
{{refend}}
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[[Category:Human proteins]]
[[Category:EC 3.1.3]]
[[Category:Genes mutated in mice]]

Latest revision as of 12:47, 5 September 2017

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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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

Model organisms have been used in the study of NDUFS3 function. A conditional knockout mouse line, called Ndufs3tm1a(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

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. ↑ 2.0 2.1 2.2 2.3 "Entrez Gene: NDUFS3 NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase)".
  3. ↑ 3.0 3.1 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. ↑ 4.0 4.1 4.2 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.
  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. PMC 2905780. 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. ↑ 19.0 19.1 19.2 19.3 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

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