NDUFS3
Identifiers
AliasesNDUFS3, CI-30, NADH:ubiquinone oxidoreductase core subunit S3, MC1DN8
External IDsOMIM: 603846 MGI: 1915599 HomoloGene: 3346 GeneCards: NDUFS3
Orthologs
SpeciesHumanMouse
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 Mbn/a
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

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]

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]

See also

References

  1. 1 2 3 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. 1 2 3 4 "Entrez Gene: NDUFS3 NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase)".
  6. 1 2 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. 1 2 3 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. S2CID 35579133.
  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.

Further reading

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