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AliasesND4, MTMT-NADH dehydrogenase, subunit 4 (complex I)
External IDsOMIM: 516003 MGI: 102498 HomoloGene: 38240 GeneCards: ND4
Gene location (Human)
Mitochondrial DNA (human)
Chr.Mitochondrial DNA (human)[1]
Bandn/aStart10,760 bp[1]
End12,137 bp[1]
RNA expression pattern
PBB GE ND4 211600 at fs.png
More reference expression data
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr M: 0.01 – 0.01 MbChr M: 0.01 – 0.01 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse
Location of the MT-ND4 gene in the human mitochondrial genome. MT-ND4 is one of the seven NADH dehydrogenase mitochondrial genes (yellow boxes).

NADH-ubiquinone oxidoreductase chain 4 is a protein that in humans is encoded by the mitochondrial gene MT-ND4.[5] The ND4 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.[6] Variations in the MT-ND4 gene are associated with age-related macular degeneration (AMD), Leber's hereditary optic neuropathy (LHON), mesial temporal lobe epilepsy (MTLE) and cystic fibrosis.[7][8][9][10]


The MT-ND4 gene is located in human mitochondrial DNA from base pair 10,760 to 12,137.[5][11] 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).[11] With respect to the MT-ND4L reading 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.[12][13] 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, hydrophobic transmembrane 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.[6]


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).[14] 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.[6]

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.[7]

Clinical significance[edit]

MT-ND4 is one of five SNPs associated with age-related macular degeneration (AMD) in Mexican Americans.[10]

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.[9]

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.[8]

MT-ND4 is downregulated in cystic fibrosis, a disease that results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) channel.[7]


MT-ND4 has been shown to have 21 binary protein-protein interactions including 15 co-complex interactions. MT-ND4 appears to interact with SP1, ZNF16, CTCF, GRB2, and ATM.[15]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000198886 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000064363 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: MT-ND4 mitochondrially encoded NADH dehydrogenase 4".
  6. ^ a b c 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.
  7. ^ a b c Valdivieso 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. PMID 17382898.
  8. ^ a b Gurses 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. PMID 24440288.
  9. ^ a b Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ, Nikoskelainen EK (December 1988). "Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy". Science. 242 (4884): 1427–30. doi:10.1126/science.3201231. PMID 3201231.
  10. ^ a b Restrepo NA, Mitchell SL, Goodloe RJ, Murdock DG, Haines JL, Crawford DC (2015). "Mitochondrial variation and the risk of age-related macular degeneration across diverse populations". Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing: 243–54. PMC 4299880. PMID 25592585.
  11. ^ a b Homo sapiens mitochondrion, complete genome. "Revised Cambridge Reference Sequence (rCRS): accession NC_012920", National Center for Biotechnology Information. Retrieved on 30 January 2016.
  12. ^ 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 (October 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.
  13. ^ "NADH-ubiquinone oxidoreductase chain 4". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  14. ^ "MT-ND4 - NADH-ubiquinone oxidoreductase chain 4 - Homo sapiens (Human)". a hub for protein information. The UniProt Consortium.
  15. ^ "21 binary interactions found for search term MT-ND4". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-08-25.

Further reading[edit]

External links[edit]