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Gene Review

MT-ND6  -  mitochondrially encoded NADH dehydrogenase 6

Homo sapiens

Synonyms: MTND6, NAD6, NADH dehydrogenase subunit 6, NADH dehydrogenase, subunit 6 (complex I), NADH-ubiquinone oxidoreductase chain 6, ...
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Disease relevance of MT-ND6

  • The mitochondrial ND6 gene is a hot spot for mutations that cause Leber's hereditary optic neuropathy [1].
  • This is the seventh mutation in the ND6 gene that causes optic neuropathy, indicating that this gene is a hot spot for LHON mutations [1].
  • RESULTS: ND1, CYTB and ND6 expression was significantly reduced in HIV+ lipodystrophic patients [2].
  • We describe a novel mutation in the ND6 gene (T14487C) in a patient with Leigh syndrome [3].
  • Physiological importance of the ND6 subunit is becoming increasingly apparent because a number of mutations leading to amino acid changes in this subunit have been found to be associated with known mitochondrial diseases [4].

High impact information on MT-ND6


Biological context of MT-ND6


Anatomical context of MT-ND6

  • Blue Native polyacrylamide gel electrophoresis showed that fibroblasts with 45% G13513A mutant load had approximately 50% of the normal amount of fully assembled complex I. Fibroblasts with greater than 97% of the ND6 G14459A mutation had only 20% fully assembled complex I, suggesting that both mutations disrupt complex I assembly or turnover [14].
  • DNA sequence analysis of the gene encoding subunit 6 of the NADH-ubiquinone-oxidoreductase complex (ND6) in human mitochondria was performed in 25 independent patients who suffer from Lebers hereditary optic neuropathy (LHON) [15].
  • The electron transfer activity of Complex I of the respiratory chain and Complex I-linked ATP synthesis were investigated in leukocytes of four males affected by Leber hereditary optic neuropathy and a mutation in the ND6 gene at nucleotide position 14,484 of mtDNA [16].

Associations of MT-ND6 with chemical compounds

  • Sequence analysis of the mtDNA of one patient was performed and showed a thymine-to-cytosine exchange at np 14498 in the ND 6 gene, leading to the replacement of an evolutionary highly conserved tyrosine by a cysteine residue [10].
  • The mutation causes a change from alanine to valine in the most conserved region of the ND6 subunit [17].
  • This ND6 np 14459 mutation changes a moderately conserved alanine to a valine at amino acid position 72 of the ND6 protein [18].
  • Analysis of 70 different amino acid sequences of the ND6 subunit indicated that the 14484 mutation affects an amino acid belonging to its most conserved region, which shows local similarities with cytochrome b regions interacting with ubiquinone or ubiquinol in complex III [19].
  • In patient 1, guanine (G) was found at the boundaries of a deleted segment spanning 8400 base pairs (bp) between the CO1 and ND6 genes [20].

Physical interactions of MT-ND6


Other interactions of MT-ND6

  • This finding shows that, in addition to ND6, the ND1 subunit gene is also a mutational hot spot for LHON [21].
  • The 10191T>C mutation in MTND3 and the 14487T>C mutation in MTND6 were present in two probands with Leigh's-like and Leigh's syndrome, respectively [22].
  • Eighteen patients carried a mitochondrial DNA (mtDNA) G11778A mutation (Arg340His in the respiratory complex I ND4 subunit), while one had a T14484C mutation (Met64Val in the ND6 subunit) [23].
  • An mtDNA mutation, 14453G-->A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome [17].
  • Two mitochondrial DNA mutations in complex I subunit genes, G14459A in ND6, and T12706C in ND5, have been associated with complex I deficiency and LD [14].

Analytical, diagnostic and therapeutic context of MT-ND6

  • The extent to which the increased variation in ND3 and ND6 is a general phenomenon applicable to all subjects rather than a finding specific to cytopathies cannot be stated with certainty given the small control group [24].
  • In the present study, the expression of the gene ND6 that is expressed from the light strand promoter (P(L)) was found to be similar in both the cell lines, as determined by RT-PCR [25].
  • Western blot analysis revealed a decrease of the 20 kDa subunit (likely ND6) and of the 30 kDa subunit (NDUFA9), which is probably due to instability attributed to the inability to form subcomplexes with ND3 [26].
  • A questionnaire on preferences and anticipated barriers, anticipated benefits, and quality of life for three in-center IHD schedules (daytime 2 hr six times/week [DHD], nocturnal 8 hr three times/week [ND3], and nocturnal 8 hr six times/week [ND6]) was administered to 100 chronic hemodialysis patients [27].
  • Antibodies raised against an internal peptide close to the N-terminus of the ND5 subunit and antibodies raised against an internal epitope of the ND6 subunit also reacted in both the immunoblotting and immunoprecipitation assays [28].


  1. The mitochondrial ND6 gene is a hot spot for mutations that cause Leber's hereditary optic neuropathy. Chinnery, P.F., Brown, D.T., Andrews, R.M., Singh-Kler, R., Riordan-Eva, P., Lindley, J., Applegarth, D.A., Turnbull, D.M., Howell, N. Brain (2001) [Pubmed]
  2. Altered mitochondrial RNA production in adipocytes from HIV-infected individuals with lipodystrophy. Galluzzi, L., Pinti, M., Guaraldi, G., Mussini, C., Troiano, L., Roat, E., Giovenzana, C., Nemes, E., Nasi, M., Orlando, G., Salomoni, P., Cossarizza, A. Antivir. Ther. (Lond.) (2005) [Pubmed]
  3. Impaired complex I assembly in a Leigh syndrome patient with a novel missense mutation in the ND6 gene. Ugalde, C., Triepels, R.H., Coenen, M.J., van den Heuvel, L.P., Smeets, R., Uusimaa, J., Briones, P., Campistol, J., Majamaa, K., Smeitink, J.A., Nijtmans, L.G. Ann. Neurol. (2003) [Pubmed]
  4. Characterization of the membrane domain subunit NuoJ (ND6) of the NADH-quinone oxidoreductase from Escherichia coli by chromosomal DNA manipulation. Kao, M.C., Di Bernardo, S., Nakamaru-Ogiso, E., Miyoshi, H., Matsuno-Yagi, A., Yagi, T. Biochemistry (2005) [Pubmed]
  5. 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]
  6. Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Coskun, P.E., Beal, M.F., Wallace, D.C. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  7. 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]
  8. The 14484 ND6 mtDNA mutation in Leber hereditary optic neuropathy does not affect fibroblast complex I activity. Cock, H.R., Cooper, J.M., Schapira, A.H. Am. J. Hum. Genet. (1995) [Pubmed]
  9. A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia. Jun, A.S., Brown, M.D., Wallace, D.C. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  10. Leber's hereditary optic neuropathy: clinical and molecular genetic results obtained in a family with a new point mutation at nucleotide position 14498 in the ND 6 gene. Leo-Kottler, B., Christ-Adler, M., Baumann, B., Zrenner, E., Wissinger, B. German journal of ophthalmology. (1996) [Pubmed]
  11. Identification of a new human mtDNA polymorphism (A14290G) in the NADH dehydrogenase subunit 6 gene. Houshmand, M., Mahmoudi, T., Panahi, M.S., Seyedena, Y., Saber, S., Ataei, M. Braz. J. Med. Biol. Res. (2006) [Pubmed]
  12. An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Johns, D.R., Neufeld, M.J., Park, R.D. Biochem. Biophys. Res. Commun. (1992) [Pubmed]
  13. The deafness-associated mitochondrial DNA mutation at position 7445, which affects tRNASer(UCN) precursor processing, has long-range effects on NADH dehydrogenase subunit ND6 gene expression. Guan, M.X., Enriquez, J.A., Fischel-Ghodsian, N., Puranam, R.S., Lin, C.P., Maw, M.A., Attardi, G. Mol. Cell. Biol. (1998) [Pubmed]
  14. Low mutant load of mitochondrial DNA G13513A mutation can cause Leigh's disease. Kirby, D.M., Boneh, A., Chow, C.W., Ohtake, A., Ryan, M.T., Thyagarajan, D., Thorburn, D.R. Ann. Neurol. (2003) [Pubmed]
  15. Mutation analysis of the ND6 gene in patients with Lebers hereditary optic neuropathy. Wissinger, B., Besch, D., Baumann, B., Fauser, S., Christ-Adler, M., Jurklies, B., Zrenner, E., Leo-Kottler, B. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  16. The mitochondrial DNA mutation ND6*14,484C associated with leber hereditary optic neuropathy, leads to deficiency of complex I of the respiratory chain. Oostra, R.J., Van Galen, M.J., Bolhuis, P.A., Bleeker-Wagemakers, E.M., Van den Bogert, C. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  17. An mtDNA mutation, 14453G-->A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome. Ravn, K., Wibrand, F., Hansen, F.J., Horn, N., Rosenberg, T., Schwartz, M. Eur. J. Hum. Genet. (2001) [Pubmed]
  18. Use of transmitochondrial cybrids to assign a complex I defect to the mitochondrial DNA-encoded NADH dehydrogenase subunit 6 gene mutation at nucleotide pair 14459 that causes Leber hereditary optic neuropathy and dystonia. Jun, A.S., Trounce, I.A., Brown, M.D., Shoffner, J.M., Wallace, D.C. Mol. Cell. Biol. (1996) [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. Detection of platelet mitochondrial DNA deletions in Kearns-Sayre syndrome. Ota, Y., Tanaka, M., Sato, W., Ohno, K., Yamamoto, T., Maehara, M., Negoro, T., Watanabe, K., Awaya, S., Ozawa, T. Invest. Ophthalmol. Vis. Sci. (1991) [Pubmed]
  21. The ND1 gene of complex I is a mutational hot spot for Leber's hereditary optic neuropathy. Valentino, M.L., Barboni, P., Ghelli, A., Bucchi, L., Rengo, C., Achilli, A., Torroni, A., Lugaresi, A., Lodi, R., Barbiroli, B., Dotti, M., Federico, A., Baruzzi, A., Carelli, V. Ann. Neurol. (2004) [Pubmed]
  22. 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]
  23. Asian-specific mtDNA backgrounds associated with the primary G11778A mutation of Leber's hereditary optic neuropathy. Sudoyo, H., Suryadi, H., Lertrit, P., Pramoonjago, P., Lyrawati, D., Marzuki, S. J. Hum. Genet. (2002) [Pubmed]
  24. Mitochondrial DNA polymorphism in disease: a possible contributor to respiratory dysfunction. Lertrit, P., Kapsa, R.M., Jean-Francois, M.J., Thyagarajan, D., Noer, A.S., Marzuki, S., Byrne, E. Hum. Mol. Genet. (1994) [Pubmed]
  25. Activation of mitochondrial promoter P(H)-binding protein in a radio-resistant Chinese hamster cell strain associated with Bcl-2. Roychoudhury, P., Ghosh, U., Bhattacharyya, N.P., Chaudhuri, K. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  26. Fulminant neurological deterioration in a neonate with Leigh syndrome due to a maternally transmitted missense mutation in the mitochondrial ND3 gene. Leshinsky-Silver, E., Lev, D., Tzofi-Berman, Z., Cohen, S., Saada, A., Yanoov-Sharav, M., Gilad, E., Lerman-Sagie, T. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  27. Patient preferences for in-center intense hemodialysis. Ramkumar, N., Beddhu, S., Eggers, P., Pappas, L.M., Cheung, A.K. Hemodialysis international. International Symposium on Home Hemodialysis (2005) [Pubmed]
  28. Multiple deficiencies of mitochondrial DNA- and nuclear-encoded subunits of respiratory NADH dehydrogenase detected with peptide- and subunit-specific antibodies in mitochondrial myopathies. Bentlage, H.A., Janssen, A.J., Chomyn, A., Attardi, G., Walker, J.E., Schägger, H., Sengers, R.C., Trijbels, F.J. Biochim. Biophys. Acta (1995) [Pubmed]
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