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NDUFS3

From Wikipedia, the free encyclopedia

NDUFS3
Identifiers
AliasesNDUFS3, CI-30, NADH:ubiquinone oxidoreductase core subunit S3, MC1DN8
External IDsOMIM: 603846; MGI: 1915599; GeneCards: NDUFS3
Enzyme activity
EC #BRENDAExPASyKEGGMetaCyc
7.1.1.2↗↗↗↗
Orthologs
DatabasesNCBI: entry; OMA: entry
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

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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

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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

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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

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References

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  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 (November 1998). "Intron based radiation hybrid mapping of 15 complex I genes of the human electron transport chain". Cytogenetics and Cell Genetics. 82 (1–2): 115–119. 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): 2392–2403. doi:10.1016/j.biochi.2013.08.032. PMID 24028823.
  7. 1 2 3 Suhane S, Berel D, Ramanujan VK (September 2011). "Biomarker signatures of mitochondrial NDUFS3 in invasive breast carcinoma". Biochemical and Biophysical Research Communications. 412 (4): 590–595. Bibcode:2011BBRC..412..590S. 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, et al. (June 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): 718–727. 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, et al. (September 2004). "NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency". The Journal of Clinical Investigation. 114 (6): 837–845. doi:10.1172/JCI20683. PMC 516258. PMID 15372108.
  11. ↑ McFarland R, Kirby DM, Fowler KJ, Ohtake A, Ryan MT, Amor DJ, et al. (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. S2CID 21076359.
  12. ↑ Haack TB, Haberberger B, Frisch EM, Wieland T, Iuso A, Gorza M, et al. (April 2012). "Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing". Journal of Medical Genetics. 49 (4): 277–283. doi:10.1136/jmedgenet-2012-100846. PMID 22499348. S2CID 3177674.
  13. ↑ Loeffen JL, Smeitink JA, Trijbels JM, Janssen AJ, Triepels RH, Sengers RC, et al. (2000). "Isolated complex I deficiency in children: clinical, biochemical and genetic aspects". Human Mutation. 15 (2): 123–134. 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): 271–286. doi:10.1016/s0005-2728(98)00033-4. PMID 9593934.

Further reading

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