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Gene Review

MT-ND4  -  mitochondrially encoded NADH dehydrogenase 4

Homo sapiens

Synonyms: MTND4, NAD4, NADH dehydrogenase subunit 4, NADH dehydrogenase, subunit 4 (complex I), NADH-ubiquinone oxidoreductase chain 4, ...
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Disease relevance of MT-ND4


Psychiatry related information on MT-ND4

  • To test this hypothesis, we assessed mtDNA deletion(s) by comparing the copy number of two regions in mtDNA -- ND1 and ND4 -- using real-time quantitative PCR in the frontal cortex of 84 subjects (30 control, 27 with bipolar disorder, and 27 with schizophrenia) [6].
  • Gene expression of mitochondrial DNA-encoded ND4 in brains of Alzheimer's disease (AD) patients and age-matched controls was measured using Northern blot [7].

High impact information on MT-ND4

  • This mutation converts the 340th amino acid of NADH dehydrogenase subunit 4 from an arginine to a histidine and eliminates an SfaNI endonuclease restriction site [8].
  • They are also significant for understanding the pathogenetic mechanism of the ND4 gene mutation associated with Leber's hereditary optic neuropathy [9].
  • We describe here a human cell line in which the enzyme lacks the mtDNA-encoded subunit ND4 due to a frameshift mutation in the gene [9].
  • Single-gene analyses indicated significant departures from neutrality in the CO1, ND4, and ND6 genes, although the data also suggested the possible operation of positive selection on the AT6 gene [10].
  • A heteroplasmic A-->G transition at nucleotide position 11696 in the ND4 gene resulted in the substitution of an isoleucine for valine at amino acid position 312 [11].

Biological context of MT-ND4

  • Stratification of the results by mutation suggests that the 11778/ND4 mutation may induce an uncoupling of cybrid respiration, whereas the other 2 mutations impair the oxygen consumption rate [12].
  • However, the frequency of ND4/11778-positive families in haplogroup J was high, which may indicate that background mutations in this haplogroup together with the ND4/11778 primary mutation promote the penetrance of LHON [13].
  • Sequence analysis of the mtDNA of the patient and his unaffected sister and niece was performed and showed a T to C missense mutation at np 11253 in the ND4 gene, leading to a replacement of an evolutionary highly conserved isoleucine by a threonine residue [2].
  • Here we report the clinical and molecular genetic findings of a LHON patient with a new mitochondrial DNA mutation at np 11253 in the ND4 gene and spontaneous recovery [2].
  • RESULTS: The mutations G3460A and G11778A in the mitochondrial genes MTND1 and MTND4, known to be causative for LHON, were found in one family each [14].

Anatomical context of MT-ND4


Associations of MT-ND4 with chemical compounds

  • The degree of reduction in the phosphocreatine concentration and phosphorylation potential and of increase in the inorganic phosphate concentration was, however, similar in the two groups with the 11778/ND4 mtDNA mutation with or without the haplogroup J [17].
  • Our results suggest that both 14484 and 14459 mutations may affect amino acids forming the interaction site of ubiquinol product, and the 14484 mutation produces a biochemical defect resembling in part that already reported for the common 11778/ND4 LHON mutation [19].
  • The phylogenetic relationships among 33 of these genera were reconstructed using mitochondrial DNA (mtDNA) sequence data from the ND3, ND4L, arginine tRNA, and ND4 genes, which we show to be evolving at the same rate [20].
  • Direct sequencing of PCR-amplified mtDNA fragments encompassing the ND4 gene of the patients disclosed a transition from guanine to adenine at nucleotide position 11778 [21].
  • We provide an independent assessment of the evolutionary history of pantherine lineage using two complete mitochondrial (mt) genes (ND2 and ND4) and the nuclear beta-fibrinogen intron 7 gene, whose utility in carnivoran phylogeny was first explored [22].

Regulatory relationships of MT-ND4

  • Both 11778/ND4 and 3460/ND1 mutations induced rotenone resistance and 11778/ND4 showed an increased K(m) for ubiquinol-2 with respect to the control group [23].

Other interactions of MT-ND4

  • Most such cases have been assumed to be caused by nuclear gene defects, but recently an increasing number have been shown to be caused by mutations in the mitochondrially encoded complex I subunit genes ND4, ND5, and ND6 [24].
  • Electron transfer properties of NADH:ubiquinone reductase in the ND1/3460 and the ND4/11778 mutations of the Leber hereditary optic neuroretinopathy (LHON) [15].
  • The mutations occur in the mtDNA genes coding for the ND1 and ND4 subunits of Complex I [15].
  • The regions presenting more sequence variants were MT-DLOOP (52%), MT-RNR2 (14%) and MT-ND4 (13%) [25].
  • RESULTS: Fourteen somatic mtDNA mutations were identified in 55% (11/20) of tumors analyzed, including 2 novel missense mutations and a frameshift mutation in ND4L, ATP6 subunit, and ND4 genes respectively [26].

Analytical, diagnostic and therapeutic context of MT-ND4


  1. Mitochondrial DNA deletions in inclusion body myositis. Oldfors, A., Larsson, N.G., Lindberg, C., Holme, E. Brain (1993) [Pubmed]
  2. Leber's hereditary optic neuropathy: clinical and molecular genetic results in a patient with a point mutation at np T11253C (isoleucine to threonine) in the ND4 gene and spontaneous recovery. Leo-Kottler, B., Luberichs, J., Besch, D., Christ-Adler, M., Fauser, S. Graefes Arch. Clin. Exp. Ophthalmol. (2002) [Pubmed]
  3. A new disease-related mutation for mitochondrial encephalopathy lactic acidosis and strokelike episodes (MELAS) syndrome affects the ND4 subunit of the respiratory complex I. Lertrit, P., Noer, A.S., Jean-Francois, M.J., Kapsa, R., Dennett, X., Thyagarajan, D., Lethlean, K., Byrne, E., Marzuki, S. Am. J. Hum. Genet. (1992) [Pubmed]
  4. Grand rounds: could occupational exposure to n-hexane and other solvents precipitate visual failure in leber hereditary optic neuropathy? Carelli, V., Franceschini, F., Venturi, S., Barboni, P., Savini, G., Barbieri, G., Pirro, E., La Morgia, C., Valentino, M.L., Zanardi, F., Violante, F.S., Mattioli, S. Environ. Health Perspect. (2007) [Pubmed]
  5. Leber's hereditary optic neuropathy (LHON/11778) with myoclonus: report of two cases. Carelli, V., Valentino, M.L., Liguori, R., Meletti, S., Vetrugno, R., Provini, F., Mancardi, G.L., Bandini, F., Baruzzi, A., Montagna, P. J. Neurol. Neurosurg. Psychiatr. (2001) [Pubmed]
  6. Quantitative analysis of mitochondrial DNA deletions in the brains of patients with bipolar disorder and schizophrenia. Kakiuchi, C., Ishiwata, M., Kametani, M., Nelson, C., Iwamoto, K., Kato, T. Int. J. Neuropsychopharmacol. (2005) [Pubmed]
  7. Gene expression of ND4, a subunit of complex I of oxidative phosphorylation in mitochondria, is decreased in temporal cortex of brains of Alzheimer's disease patients. Fukuyama, R., Hatanpää, K., Rapoport, S.I., Chandrasekaran, K. Brain Res. (1996) [Pubmed]
  8. A mitochondrial DNA mutation as a cause of Leber's hereditary optic neuropathy. Singh, G., Lott, M.T., Wallace, D.C. N. Engl. J. Med. (1989) [Pubmed]
  9. Lack of assembly of mitochondrial DNA-encoded subunits of respiratory NADH dehydrogenase and loss of enzyme activity in a human cell mutant lacking the mitochondrial ND4 gene product. Hofhaus, G., Attardi, G. EMBO J. (1993) [Pubmed]
  10. Comparative genomics and the evolution of human mitochondrial DNA: assessing the effects of selection. Elson, J.L., Turnbull, D.M., Howell, N. Am. J. Hum. Genet. (2004) [Pubmed]
  11. Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia. De Vries, D.D., Went, L.N., Bruyn, G.W., Scholte, H.R., Hofstra, R.M., Bolhuis, P.A., van Oost, B.A. Am. J. Hum. Genet. (1996) [Pubmed]
  12. Severe impairment of complex I-driven adenosine triphosphate synthesis in leber hereditary optic neuropathy cybrids. Baracca, A., Solaini, G., Sgarbi, G., Lenaz, G., Baruzzi, A., Schapira, A.H., Martinuzzi, A., Carelli, V. Arch. Neurol. (2005) [Pubmed]
  13. mtDNA haplotype analysis in Finnish families with leber hereditary optic neuroretinopathy. Lamminen, T., Huoponen, K., Sistonen, P., Juvonen, V., Lahermo, P., Aula, P., Nikoskelainen, E., Savontaus, M.L. Eur. J. Hum. Genet. (1997) [Pubmed]
  14. Leber's hereditary optic neuropathy with molecular characterization in two Indian families. Verma, I.C., Bijarnia, S., Saxena, R., Kohli, S., Puri, R.D., Thomas, E., Chowdhary, D., Jha, S.N., Grover, A.K. Indian journal of ophthalmology. (2005) [Pubmed]
  15. Electron transfer properties of NADH:ubiquinone reductase in the ND1/3460 and the ND4/11778 mutations of the Leber hereditary optic neuroretinopathy (LHON). Majander, A., Huoponen, K., Savontaus, M.L., Nikoskelainen, E., Wikström, M. FEBS Lett. (1991) [Pubmed]
  16. Secondary metabolic effects in complex I deficiency. Esteitie, N., Hinttala, R., Wibom, R., Nilsson, H., Hance, N., Naess, K., Teär-Fahnehjelm, K., von Döbeln, U., Majamaa, K., Larsson, N.G. Ann. Neurol. (2005) [Pubmed]
  17. 'Secondary' 4216/ND1 and 13708/ND5 Leber's hereditary optic neuropathy mitochondrial DNA mutations do not further impair in vivo mitochondrial oxidative metabolism when associated with the 11778/ND4 mitochondrial DNA mutation. Lodi, R., Montagna, P., Cortelli, P., Iotti, S., Cevoli, S., Carelli, V., Barbiroli, B. Brain (2000) [Pubmed]
  18. MtDNA mutations associated with Leber's hereditary optic neuropathy: studies on cytoplasmic hybrid (cybrid) cells. Vergani, L., Martinuzzi, A., Carelli, V., Cortelli, P., Montagna, P., Schievano, G., Carrozzo, R., Angelini, C., Lugaresi, E. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  19. Biochemical features of mtDNA 14484 (ND6/M64V) point mutation associated with Leber's hereditary optic neuropathy. Carelli, V., Ghelli, A., Bucchi, L., Montagna, P., De Negri, A., Leuzzi, V., Carducci, C., Lenaz, G., Lugaresi, E., Degli Esposti, M. Ann. Neurol. (1999) [Pubmed]
  20. Molecular systematics and paleobiogeography of the South American sigmodontine rodents. Engel, S.R., Hogan, K.M., Taylor, J.F., Davis, S.K. Mol. Biol. Evol. (1998) [Pubmed]
  21. Mitochondrial DNA mutation in Leber's hereditary optic neuropathy. Yen, M.Y., Yen, T.C., Pang, C.Y., Liu, J.H., Wei, Y.H. Invest. Ophthalmol. Vis. Sci. (1992) [Pubmed]
  22. Phylogenetic studies of pantherine cats (Felidae) based on multiple genes, with novel application of nuclear beta-fibrinogen intron 7 to carnivores. Yu, L., Zhang, Y.P. Mol. Phylogenet. Evol. (2005) [Pubmed]
  23. Changes in mitochondrial complex I activity and coenzyme Q binding site in Leber's hereditary optic neuropathy (LHON). Ghelli, A., Degli Esposti, M., Carelli, V., Lenaz, G. Mol. Aspects Med. (1997) [Pubmed]
  24. De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency. McFarland, R., Kirby, D.M., Fowler, K.J., Ohtake, A., Ryan, M.T., Amor, D.J., Fletcher, J.M., Dixon, J.W., Collins, F.A., Turnbull, D.M., Taylor, R.W., Thorburn, D.R. Ann. Neurol. (2004) [Pubmed]
  25. Identification of somatic and germline mitochondrial DNA sequence variants in prostate cancer patients. Gómez-Zaera, M., Abril, J., González, L., Aguiló, F., Condom, E., Nadal, M., Nunes, V. Mutat. Res. (2006) [Pubmed]
  26. Significance of somatic mutations and content alteration of mitochondrial DNA in esophageal cancer. Tan, D.J., Chang, J., Liu, L.L., Bai, R.K., Wang, Y.F., Yeh, K.T., Wong, L.J. BMC Cancer (2006) [Pubmed]
  27. Homoplasmic and exclusive ND4 gene mutation in Japanese pedigrees with Leber's disease. Nakamura, M., Fujiwara, Y., Yamamoto, M. Invest. Ophthalmol. Vis. Sci. (1993) [Pubmed]
  28. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Wallace, D.C., Singh, G., Lott, M.T., Hodge, J.A., Schurr, T.G., Lezza, A.M., Elsas, L.J., Nikoskelainen, E.K. Science (1988) [Pubmed]
  29. New variants in the mitochondrial genomes of schizophrenic patients. Martorell, L., Segués, T., Folch, G., Valero, J., Joven, J., Labad, A., Vilella, E. Eur. J. Hum. Genet. (2006) [Pubmed]
  30. Conformational mutation in human mtDNA detected by direct sequencing of enzymatically amplified DNA. Vigilant, L., Stoneking, M., Wilson, A.C. Nucleic Acids Res. (1988) [Pubmed]
  31. The Mutant Human ND4 Subunit of Complex I Induces Optic Neuropathy in the Mouse. Qi, X., Sun, L., Lewin, A.S., Hauswirth, W.W., Guy, J. Invest. Ophthalmol. Vis. Sci. (2007) [Pubmed]
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