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NADH dehydrogenase, subunit 4 (complex I)
Symbols ND4 ; MTND4
External IDs OMIM516003 MGI102498 HomoloGene38240 ChEMBL: 4499 GeneCards: ND4 Gene
RNA expression pattern
PBB GE ND4 211600 at tn.png
More reference expression data
Species Human Mouse
Entrez 4538 17719
Ensembl ENSG00000198886 ENSMUSG00000064363
UniProt P03905 P03911
RefSeq (mRNA) n/a n/a
RefSeq (protein) n/a NP_904337
Location (UCSC) Chr MT:
0.01 – 0.01 Mb
Chr MT:
0.01 – 0.01 Mb
PubMed search [1] [2]

NADH-ubiquinone oxidoreductase chain 4 is a protein that in humans is encoded by the mitochondrial gene MT-ND4.[1] 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.[2] 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.[3][4][5][6]


MT-ND4 is located in mitochondrial DNA from base pair 10,760 to 12,137.[1] The MT-ND4 gene produces a 52 kDa protein composed of 459 amino acids.[7][8] 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.[2]


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).[9] 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]

Clinical significance[edit]

MT-ND4 is one of five SNPs associated with age-related macular degeneration (AMD) in Mexican Americans.[6]

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]

MT-ND4 is downregulated in cystic fibrosis, a disease that results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) channel.[3]


  1. ^ a b "Entrez Gene: MT-ND4 mitochondrially encoded NADH dehydrogenase 4". 
  2. ^ a b c Pratt, Donald Voet, Judith G. Voet, Charlotte W. (2013). "18". Fundamentals of biochemistry : life at the molecular level (4th ed. ed.). Hoboken, NJ: Wiley. pp. 581–620. ISBN 9780470547847. 
  3. ^ a b c Valdivieso, AG; Marcucci, F; Taminelli, G; Guerrico, AG; Alvarez, S; Teiber, ML; Dankert, MA; Santa-Coloma, TA (11 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. 
  4. ^ a b Gurses, C; Azakli, H; Alptekin, A; Cakiris, A; Abaci, N; Arikan, M; Kursun, O; Gokyigit, A; Ustek, D (1 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. 
  5. ^ a b Wallace, DC; Singh, G; Lott, MT; Hodge, JA; Schurr, TG; Lezza, AM; Elsas LJ, 2nd; Nikoskelainen, EK (9 December 1988). "Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy.". Science (New York, N.Y.) 242 (4884): 1427–30. doi:10.1126/science.3201231. PMID 3201231. 
  6. ^ 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. PMID 25592585. 
  7. ^ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS et al. (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. 
  8. ^ "NADH-ubiquinone oxidoreductase chain 4". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). 
  9. ^ "MT-ND4 - NADH-ubiquinone oxidoreductase chain 4 - Homo sapiens (Human)". a hub for protein information. The UniProt Consortium. 

Further reading[edit]

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