NDUFA4 explained

NDUFA4, mitochondrial complex associated is a protein that in humans is encoded by the NDUFA4 gene.^[1] The NDUFA4 protein was first described to be 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.^[2] However, recent research has described NDUFA4 as a subunit of cytochrome c oxidase. Mutations in the NDUFA4 gene are associated with Leigh's syndrome.

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. The NDUFA4 gene produces a 9.4 kDa protein composed of 81 amino acids.^{[3] [4]}

NDUFA4 has traditionally been defined as a subunit of the enzyme NADH dehydrogenase (ubiquinone) (Complex I), the largest of the respiratory complexes.

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.^[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.^{[6] [7]}

Interactions

NDUFA4 has many protein-protein interactions, including ubiquitin proteins such as ubiquitin C and UBL4A, as well as CUL3 and PARK7.^[1]

Further reading

• Loeffen JL, Triepels RH, van den Heuvel LP, Schuelke M, Buskens CA, Smeets RJ, Trijbels JM, Smeitink JA . 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 . Dec 1998 . 9878551 . 10.1006/bbrc.1998.9786 .
• Hayashi T, Ishimori C, Takahashi-Niki K, Taira T, Kim YC, Maita H, Maita C, Ariga H, Iguchi-Ariga SM . DJ-1 binds to mitochondrial complex I and maintains its activity . Biochemical and Biophysical Research Communications . 390 . 3 . 667–72 . Dec 2009 . 19822128 . 10.1016/j.bbrc.2009.10.025 . 2115/42484 . free .
• Murray J, Zhang B, Taylor SW, Oglesbee D, Fahy E, Marusich MF, Ghosh SS, Capaldi RA . The subunit composition of the human NADH dehydrogenase obtained by rapid one-step immunopurification . The Journal of Biological Chemistry . 278 . 16 . 13619–22 . Apr 2003 . 12611891 . 10.1074/jbc.C300064200 . free .
• 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 . NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease . Cell Reports . 3 . 6 . 1795–805 . Jun 2013 . 23746447 . 3701321 . 10.1016/j.celrep.2013.05.005 .
• Kim JW, Lee Y, Kang HB, Chose YK, Chung TW, Chang SY, Lee KS, Choe IS . Cloning of the human cDNA sequence encoding the NADH:ubiquinone oxidoreductase MLRQ subunit . Biochemistry and Molecular Biology International . 43 . 3 . 669–75 . Oct 1997 . 9352085 . 10.1080/15216549700204471. 11674131 . free .
• Lamhonwah AM, Tein I . Novel localization of OCTN1, an organic cation/carnitine transporter, to mammalian mitochondria . Biochemical and Biophysical Research Communications . 345 . 4 . 1315–25 . Jul 2006 . 16729965 . 10.1016/j.bbrc.2006.05.026 .

Notes and References

1. Web site: Entrez Gene: NDUFA4, mitochondrial complex associated. 2015-03-24.
2. Book: Pratt. Donald Voet, Judith G. Voet, Charlotte W.. Fundamentals of biochemistry : life at the molecular level. 2013. Wiley. Hoboken, NJ. 9780470547847. 18 . 581–620. 4th.
3. 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 . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–53 . Oct 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
4. Web site: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4 ]. Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) .
5. Balsa E, Marco R, Perales-Clemente E, Szklarczyk R, Calvo E, Landázuri MO, Enríquez JA . NDUFA4 is a subunit of complex IV of the mammalian electron transport chain . Cell Metabolism . 16 . 3 . 378–386 . Sep 2012 . 22902835 . 10.1016/j.cmet.2012.07.015 . free .
6. Web site: Leigh syndrome. Genetics Home Reference. U.S. National Library of Medicine. 30 March 2015.
7. 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 . NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease . Cell Reports . 3 . 6 . 1795–805 . Jun 2013 . 23746447 . 3701321 . 10.1016/j.celrep.2013.05.005 .