Biology:NDUFS3

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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]

See also

References

  1. ↑ "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. Nov 1998. 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)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4722. 
  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 "Biomarker signatures of mitochondrial NDUFS3 in invasive breast carcinoma". Biochemical and Biophysical Research Communications 412 (4): 590–5. Sep 2011. doi:10.1016/j.bbrc.2011.08.003. PMID 21867691. 
  5. ↑ "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. Jun 2009. doi:10.1016/j.ajhg.2009.04.020. PMID 19463981. 
  6. ↑ "Granzyme A activates another way to die". Immunological Reviews 235 (1): 93–104. May 2010. doi:10.1111/j.0105-2896.2010.00902.x. PMID 20536557. 
  7. ↑ "NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency". The Journal of Clinical Investigation 114 (6): 837–45. Sep 2004. doi:10.1172/JCI20683. PMID 15372108. 
  8. ↑ "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. Jan 2004. doi:10.1002/ana.10787. PMID 14705112. 
  9. ↑ "Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing". Journal of Medical Genetics 49 (4): 277–83. Apr 2012. doi:10.1136/jmedgenet-2012-100846. PMID 22499348. https://epub.ub.uni-muenchen.de/21895/1/oa_21895.pdf. 
  10. ↑ "Isolated complex I deficiency in children: clinical, biochemical and genetic aspects". Human Mutation 15 (2): 123–34. 2000. doi:10.1002/(SICI)1098-1004(200002)15:2<123::AID-HUMU1>3.0.CO;2-P. PMID 10649489. 
  11. ↑ "Respiratory chain complex I deficiency". American Journal of Medical Genetics 106 (1): 37–45. 2001. doi:10.1002/ajmg.1397. PMID 11579423. 
  12. ↑ "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. May 1998. doi:10.1016/s0005-2728(98)00033-4. PMID 9593934. 

Further reading



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