NDUFA9

NDUFA9
Identifiers
Aliases NDUFA9, CC6, CI-39k, CI39k, NDUFS2L, SDR22E1, NADH:ubiquinone oxidoreductase subunit A9
External IDs MGI: 1913358 HomoloGene: 3666 GeneCards: NDUFA9
RNA expression pattern


More reference expression data
Orthologs
Species Human Mouse
Entrez

4704

66108

Ensembl

ENSG00000139180

ENSMUSG00000000399

UniProt

Q16795

Q9DC69

RefSeq (mRNA)

NM_005002

NM_025358

RefSeq (protein)

NP_004993.1

NP_079634.2

Location (UCSC) Chr 12: 4.65 – 4.69 Mb Chr 6: 126.82 – 126.85 Mb
PubMed search [1] [2]
Wikidata
View/Edit HumanView/Edit Mouse

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9 is an enzyme that in humans is encoded by the NDUFA9 gene.[3][4][5] The NDUFA9 protein is a subunit of NADH:ubiquinone oxidoreductase (Complex I of the electron transport chain), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[6][7] Mutations in NADH dehydrogenase (ubiquinone), also known as Complex I, frequently lead to complex neurodegenerative diseases such as Leigh's syndrome. In the case of NDUFA9, a mutation to the MT-ND3 gene might interrupt their interaction and formation of subcomplexes, compromising Complex I function and leading to disease.[8]

Structure

The NDUFA9 gene is located on the p arm of chromosome 12 in position 13.3 and spans 38,457 base pairs.[3] The gene produces a 42.5 kDa protein composed of 377 amino acids.[9] NDUFA9 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centers and the NADH binding site.[6] It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane. NDUFA9 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I, but it is an accessory subunit that is believed not to be involved in catalysis.[10] The predicted secondary structure is primarily alpha helix, but the carboxy-terminal half of the protein has high potential to adopt a coiled-coil form. The amino-terminal part contains a putative beta sheet rich in hydrophobic amino acids that may serve as mitochondrial import signal.[3][7][11]

Function

The human NDUFA9 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone.[3] NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[6]

Clinical significance

Decreased expression of NDUFA9 is associated with Leigh's syndrome, a severe neurological disorder that typically arises in the first year of life, is characterized by progressive loss of mental and movement abilities, and typically results in death within a couple of years, usually due to respiratory failure. A mutation in the MT-ND3 gene (tyrosine to cytosine at the 10191 position) results in a substitution of serine for proline, which may introduce instability of Complex I due to the inability form subcomplexes between MT-ND3 and NDUFA9. However, this genetic identification may not be suitable for prenatal testing because of the mutation's age and tissue dependence.[8]

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. 1 2 3 4 "Entrez Gene: NDUFA9 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 9".
  4. ↑ Baens M, Chaffanet M, Cassiman JJ, van den Berghe H, Marynen P (Apr 1993). "Construction and evaluation of a hncDNA library of human 12p transcribed sequences derived from a somatic cell hybrid". Genomics. 16 (1): 214–8. doi:10.1006/geno.1993.1161. PMID 8486360.
  5. ↑ Persson B, Kallberg Y, Bray JE, Bruford E, Dellaporta SL, Favia AD, Duarte RG, Jörnvall H, Kavanagh KL, Kedishvili N, Kisiela M, Maser E, Mindnich R, Orchard S, Penning TM, Thornton JM, Adamski J, Oppermann U (Mar 2009). "The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative". Chemico-Biological Interactions. 178 (1-3): 94–8. doi:10.1016/j.cbi.2008.10.040. PMC 2896744Freely accessible. PMID 19027726.
  6. 1 2 3 Voet D, Voet JG, Pratt CW (2013). "Chapter 18". Fundamentals of biochemistry: life at the molecular level (4th ed.). Hoboken, NJ: Wiley. pp. 581–620. ISBN 978-0-470-54784-7.
  7. 1 2 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.
  8. 1 2 Leshinsky-Silver E, Lev D, Tzofi-Berman Z, Cohen S, Saada A, Yanoov-Sharav M, Gilad E, Lerman-Sagie T (Aug 2005). "Fulminant neurological deterioration in a neonate with Leigh syndrome due to a maternally transmitted missense mutation in the mitochondrial ND3 gene". Biochemical and Biophysical Research Communications. 334 (2): 582–7. doi:10.1016/j.bbrc.2005.06.134. PMID 16023078.
  9. ↑ "NDUFA9 - NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  10. ↑ "NDUFA9 - NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial". UniProt.org. The UniProt Consortium.
  11. ↑ Ton C, Hwang DM, Dempsey AA, Liew CC (Dec 1997). "Identification and primary structure of five human NADH-ubiquinone oxidoreductase subunits". Biochemical and Biophysical Research Communications. 241 (2): 589–94. doi:10.1006/bbrc.1997.7707. PMID 9425316.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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