File:Map of the human mitochondrial genome.svgLocation of the MT-ND4 gene in the human mitochondrial genome. MT-ND4 is one of the seven NADH dehydrogenase mitochondrial genes (yellow boxes).
The MT-ND4 gene is located in human mitochondrial DNA from base pair 10,760 to 12,137.[1][7] An unusual feature of the human MT-ND4 gene is the 7-nucleotide gene overlap of its first three codons (5'-ATG CTA AAA-3' coding for amino acids Met-Leu-Lys) with the last three codons of the MT-ND4L gene (5'-CAA TGC TAA-3' coding for Gln, Cys and Stop).[7] With respect to the MT-ND4Lreading frame (+1), the MT-ND4 gene starts in the +3 reading frame: [CAA][TGC][TAA]AA versus CA[ATG][CTA][AAA].
The MT-ND4 gene produces a 52 kDa protein composed of 459 amino acids.[8][9] MT-ND4 is one of seven mitochondrially-encoded subunits of the enzyme NADH dehydrogenase (ubiquinone). Also known as Complex I, it is the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobictransmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centres and the NADH binding site. MT-ND4 and the rest of the mitochondrially encoded subunits are the most hydrophobic of the subunits of Complex I and form the core of the transmembrane region.[2]
Function
MT-ND4 is a subunit of the respiratory chain Complex I that is believed to belong to the minimal assembly of core proteins required to catalyze NADH dehydrogenation and electron transfer to ubiquinone (coenzyme Q10).[10] 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.[2]
Studies in cystic fibrosis cases suggest that MT-ND4 expression is indirectly upregulated by the cystic fibrosis transmembrane conductance regulator (CFTR) channel chloride transport activity. Channel flow double-electrode (CFDE) cells ectopically expressing wild-type CFTR channels were used to test the effect of CFTR chloride transport inhibitors glibenclamide and CFTR(inh)172 and demonstrated a reduction in MT-ND4 expression.[3]
Leber's hereditary optic neuropathy (LHON) correlates with a mutation in the MT-ND4 gene in multiple families. The mutation at codon 340 results in the elimination of an Sfa NI site by the conversion of a highly conserved arginine to a histidine. This provides a simple diagnostic test by which to identify LHON, a maternally inherited disease that results in optic nerve degeneration and cardiac dysrythmia.[5]
Amino acid changes in MT-ND4, MT-ND5 and MT-ATP8 resulting from mutations at the 11994, 8502 and 13,231 bp of mtDNA are significantly correlated in mesial temporal lobe epilepsy (MTLE) patients with hippocampal sclerosis. The 11994 C>T mutation to the MT-ND4 gene results in a Thr to Ile shift at the 412 position. Genome analysis has never been used in MTLE cases and could provide another diagnostic method in the disease.[4]
↑ 2.02.12.2Pratt, 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. ISBN9780470547847.
↑ 3.03.13.2Valdivieso AG, Marcucci F, Taminelli G, Guerrico AG, Alvarez S, Teiber ML, Dankert MA, Santa-Coloma TA (May 2007). "The expression of the mitochondrial gene MT-ND4 is downregulated in cystic fibrosis". Biochemical and Biophysical Research Communications. 356 (3): 805–9. doi:10.1016/j.bbrc.2007.03.057. PMID17382898.
↑ 4.04.1Gurses C, Azakli H, Alptekin A, Cakiris A, Abaci N, Arikan M, Kursun O, Gokyigit A, Ustek D (April 2014). "Mitochondrial DNA profiling via genomic analysis in mesial temporal lobe epilepsy patients with hippocampal sclerosis". Gene. 538 (2): 323–7. doi:10.1016/j.gene.2014.01.030. PMID24440288.
Andreu AL, Tanji K, Bruno C, Hadjigeorgiou GM, Sue CM, Jay C, Ohnishi T, Shanske S, Bonilla E, DiMauro S (June 1999). "Exercise intolerance due to a nonsense mutation in the mtDNA ND4 gene". Annals of Neurology. 45 (6): 820–3. PMID10360780.
Torroni A, Achilli A, Macaulay V, Richards M, Bandelt HJ (June 2006). "Harvesting the fruit of the human mtDNA tree". Trends in Genetics. 22 (6): 339–45. doi:10.1016/j.tig.2006.04.001. PMID16678300.
Lu X, Walker T, MacManus JP, Seligy VL (July 1992). "Differentiation of HT-29 human colonic adenocarcinoma cells correlates with increased expression of mitochondrial RNA: effects of trehalose on cell growth and maturation". Cancer Research. 52 (13): 3718–25. PMID1377597.
Marzuki S, Noer AS, Lertrit P, Thyagarajan D, Kapsa R, Utthanaphol P, Byrne E (December 1991). "Normal variants of human mitochondrial DNA and translation products: the building of a reference data base". Human Genetics. 88 (2): 139–45. doi:10.1007/bf00206061. PMID1757091.
Majander A, Huoponen K, Savontaus ML, Nikoskelainen E, Wikström M (November 1991). "Electron transfer properties of NADH:ubiquinone reductase in the ND1/3460 and the ND4/11778 mutations of the Leber hereditary optic neuroretinopathy (LHON)". FEBS Letters. 292 (1–2): 289–92. doi:10.1016/0014-5793(91)80886-8. PMID1959619.
Kormann BA, Schuster H, Berninger TA, Leo-Kottler B (November 1991). "Detection of the G to A mitochondrial DNA mutation at position 11778 in German families with Leber's hereditary optic neuropathy". Human Genetics. 88 (1): 98–100. doi:10.1007/BF00204937. PMID1959931.
Chomyn A, Cleeter MW, Ragan CI, Riley M, Doolittle RF, Attardi G (October 1986). "URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit". Science. 234 (4776): 614–8. doi:10.1126/science.3764430. PMID3764430.
Chomyn A, Mariottini P, Cleeter MW, Ragan CI, Matsuno-Yagi A, Hatefi Y, Doolittle RF, Attardi G (1985). "Six unidentified reading frames of human mitochondrial DNA encode components of the respiratory-chain NADH dehydrogenase". Nature. 314 (6012): 592–7. doi:10.1038/314592a0. PMID3921850.
Brown WM, Prager EM, Wang A, Wilson AC (1982). "Mitochondrial DNA sequences of primates: tempo and mode of evolution". Journal of Molecular Evolution. 18 (4): 225–39. doi:10.1007/BF01734101. PMID6284948.
Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG (April 1981). "Sequence and organization of the human mitochondrial genome". Nature. 290 (5806): 457–65. doi:10.1038/290457a0. PMID7219534.
Montoya J, Ojala D, Attardi G (April 1981). "Distinctive features of the 5'-terminal sequences of the human mitochondrial mRNAs". Nature. 290 (5806): 465–70. doi:10.1038/290465a0. PMID7219535.
Sudoyo H, Sitepu M, Malik S, Poesponegoro HD, Marzuki S (1999). "Leber's hereditary optic neuropathy in Indonesia: two families with the mtDNA 11778G>A and 14484T>C mutations". Human Mutation. Suppl 1: S271–4. doi:10.1002/humu.1380110186. PMID9452107.
Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N (October 1999). "Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA". Nature Genetics. 23 (2): 147. doi:10.1038/13779. PMID10508508.
Ingman M, Kaessmann H, Pääbo S, Gyllensten U (December 2000). "Mitochondrial genome variation and the origin of modern humans". Nature. 408 (6813): 708–13. doi:10.1038/35047064. PMID11130070.
Thorburn DR, Rahman S (1993–2015). "Mitochondrial DNA-Associated Leigh Syndrome and NARP". In Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Dolan CR, Fong CT, Smith RJ, Stephens K. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle.
