NDUFA4

NDUFA4, mitochondrial complex associated is a protein that in humans is encoded by the NDUFA4 gene.[4] The NDUFA3 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[5] Mutations in the NDUFA4 gene are associated with Leigh's syndrome.[4]

NDUFA4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1LEG, 1LEK, 1MWA, 2CKB
Identifiers
Aliases	NDUFA4, CI-9k, CI-MLRQ, MLRQ, mitochondrial complex associated, COXFA4, NDUFA4 mitochondrial complex associated
External IDs	OMIM: 603833 MGI: 107686 HomoloGene: 37629 GeneCards: NDUFA4
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7p21.3 Start 10,931,943 bp[1] End 10,940,153 bp[1]
Gene ontology Molecular function • NADH dehydrogenase (ubiquinone) activity • cytochrome-c oxidase activity • GO:0001948 protein binding • GO:0032403 macromolecular complex binding Cellular component • mitochondrial inner membrane • mitochondrial respiratory chain complex I • electron transport • membrane • mitochondrion • mitochondrial respiratory chain complex IV Biological process • oxidation-reduction process • mitochondrial electron transport, NADH to ubiquinone • hydrogen ion transmembrane transport • mitochondrial electron transport, cytochrome c to oxygen Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4697	17992
Ensembl	ENSG00000189043	n/a
UniProt	O00483	Q62425
RefSeq (mRNA)	NM_002489	NM_010886
RefSeq (protein)	NP_002480	NP_035016
Location (UCSC)	Chr 7: 10.93 – 10.94 Mb	n/a
PubMed search	[2]	[3]
Wikidata
View/Edit Human View/Edit Mouse

Structure

The NDUFA4 gene is located on the p arm of chromosome 7 at position 21.3 with a total length of 8,234 base pairs.[4] The NDUFA4 gene produces a 9.4 kDa protein composed of 81 amino acids.[6][7]

NDUFA4 has traditionally been defined as a subunit of the enzyme NADH dehydrogenase (ubiquinone) (Complex I), the largest of the respiratory complexes. The structure of Complex I 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.[5] 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:ubiquinone oxidoreductase complex at the inner mitochondrial membrane.[4]

More recent research has demonstrated that no perturbation of Complex I occurs upon NDUFA4 deletion, calling into question its role in this complex. It has been demonstrated that NDUFA4 plays a role in Complex IV function and biogenesis, however, with some authors suggesting that the NDUFA4 gene be renamed and the structure of both Complex I and Complex IV be re-evaluated.[8]

Function

The human NDUFA1 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. Mammalian complex I of mitochondrial respiratory chain is composed of 45 different subunits; the protein encoded by this gene belongs to the complex I 9kDa subunit family and it has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain.[4] Initially, 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.[5]

Clinical significance

Mutations in the NDUFA4 gene can result in Leigh's syndrome, a severe neurological disorder that typically arises in the first year of life. Disruption of Complex IV, also called cytochrome c oxidase or COX, is the most common cause of Leigh syndrome. Given that NDUFA4 has only recently been identified as a subunit of Complex IV rather than Complex I, patients with previously unexplained COX deficiencies could be genetically tested for NDUFA4 mutations.[4][9][10]

Interactions

NDUFA4 has many protein-protein interactions, including ubiquitin proteins such as ubiquitin C and UBL4A, as well as CUL3 and PARK7.[4]

References

1. GRCh38: Ensembl release 89: ENSG00000189043 - 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. "Entrez Gene: NDUFA4, mitochondrial complex associated". Retrieved 2015-03-24.
5. Pratt, Donald Voet, Judith G. Voet, Charlotte W. (2013). "18". Fundamentals of biochemistry : life at the molecular level (4th ed.). Hoboken, NJ: Wiley. pp. 581–620. ISBN 9780470547847.
6. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
7. "NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
8. Balsa E, Marco R, Perales-Clemente E, Szklarczyk R, Calvo E, Landázuri MO, Enríquez JA (Sep 2012). "NDUFA4 is a subunit of complex IV of the mammalian electron transport chain". Cell Metabolism. 16 (3): 378–386. doi:10.1016/j.cmet.2012.07.015. PMID 22902835.
9. "Leigh syndrome". Genetics Home Reference. U.S. National Library of Medicine. Retrieved 30 March 2015.
10. Pitceathly RD, Rahman S, Wedatilake Y, Polke JM, Cirak S, Foley AR, Sailer A, Hurles ME, Stalker J, Hargreaves I, Woodward CE, Sweeney MG, Muntoni F, Houlden H, Taanman JW, Hanna MG (Jun 2013). "NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease". Cell Reports. 3 (6): 1795–805. doi:10.1016/j.celrep.2013.05.005. PMC 3701321. PMID 23746447.

Further reading

• Loeffen JL, Triepels RH, van den Heuvel LP, Schuelke M, Buskens CA, Smeets RJ, Trijbels JM, Smeitink JA (Dec 1998). "cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase: human complex I cDNA characterization completed". Biochemical and Biophysical Research Communications. 253 (2): 415–22. doi:10.1006/bbrc.1998.9786. PMID 9878551.
• Hayashi T, Ishimori C, Takahashi-Niki K, Taira T, Kim YC, Maita H, Maita C, Ariga H, Iguchi-Ariga SM (Dec 2009). "DJ-1 binds to mitochondrial complex I and maintains its activity" (PDF). Biochemical and Biophysical Research Communications. 390 (3): 667–72. doi:10.1016/j.bbrc.2009.10.025. PMID 19822128.
• Murray J, Zhang B, Taylor SW, Oglesbee D, Fahy E, Marusich MF, Ghosh SS, Capaldi RA (Apr 2003). "The subunit composition of the human NADH dehydrogenase obtained by rapid one-step immunopurification". The Journal of Biological Chemistry. 278 (16): 13619–22. doi:10.1074/jbc.C300064200. PMID 12611891.
• Pitceathly RD, Rahman S, Wedatilake Y, Polke JM, Cirak S, Foley AR, Sailer A, Hurles ME, Stalker J, Hargreaves I, Woodward CE, Sweeney MG, Muntoni F, Houlden H, Taanman JW, Hanna MG (Jun 2013). "NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease". Cell Reports. 3 (6): 1795–805. doi:10.1016/j.celrep.2013.05.005. PMC 3701321. PMID 23746447.
• Kim JW, Lee Y, Kang HB, Chose YK, Chung TW, Chang SY, Lee KS, Choe IS (Oct 1997). "Cloning of the human cDNA sequence encoding the NADH:ubiquinone oxidoreductase MLRQ subunit". Biochemistry and Molecular Biology International. 43 (3): 669–75. doi:10.1080/15216549700204471. PMID 9352085.
• Lamhonwah AM, Tein I (Jul 2006). "Novel localization of OCTN1, an organic cation/carnitine transporter, to mammalian mitochondria". Biochemical and Biophysical Research Communications. 345 (4): 1315–25. doi:10.1016/j.bbrc.2006.05.026. PMID 16729965.

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