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Gene Review

MT-ND1  -  mitochondrially encoded NADH dehydrogenase 1

Homo sapiens

Synonyms: MTND1, NAD1, NADH dehydrogenase subunit 1, NADH dehydrogenase, subunit 1 (complex I), NADH-ubiquinone oxidoreductase chain 1, ...
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Disease relevance of MT-ND1

  • Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees [1].
  • Expression of the RBMY1A, RBMY1H and RBMII genes was lacking in all prostate cancer cell lines but after demethylation the expression of all 3 was restored in the ND1, DU-145 and LNCaP cell lines [2].
  • A novel combination of mitochondrial tRNA and ND1 gene mutations in a syndrome with MELAS, cardiomyopathy, and diabetes mellitus [3].
  • We now report identification by sequencing, restriction endonuclease analyses, and clonal analyses of a heteroplasmic missense A to G base pair substitution at nucleotide position 3796 (A3796G) in the gene encoding the ND1 subunit of mitochondrial complex I in a patient with adult-onset dystonia, spasticity, and core-type myopathy [4].
  • RESULTS: ND1, CYTB and ND6 expression was significantly reduced in HIV+ lipodystrophic patients [5].

Psychiatry related information on MT-ND1

  • 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].
  • Heteroplasmic mitochondrial DNA 3310 mutation in NADH dehydrogenase subunit 1 associated with type 2 diabetes, hypertrophic cardiomyopathy, and mental retardation in a single patient [7].
  • Our results suggest that a relative excess of nonsynonymous mutations in MTND genes in supercluster JTWIX is associated with an increased risk of PD and the disease progression to dementia [8].

High impact information on MT-ND1


Chemical compound and disease context of MT-ND1

  • Mitochondrial respiratory function in a patient with maternally inherited type 2 diabetes mellitus and hypertrophic cardiomyopathy associated with heteroplasmic mitochondrial DNA (mtDNA) C3310T mutation, which replaces the second amino acid of NADH dehydrogenase 1 (ND1) from a hydrophobic Proline to a hydrophilic Serine, was investigated [14].

Biological context of MT-ND1


Anatomical context of MT-ND1

  • Short-chain ubiquinone analogues act as electron acceptors and as inhibitors in the lymphoblast mitochondria of ND1/3460 mutants, which indicates structural changes in the ubiquinone-binding domain of Complex I in this mutant [19].
  • As complex I genes are the most vulnerable part of mtDNA we analyzed the mitochondrial MTND1 and MTND2 genes of 10 substantia nigra and 85 platelet samples from PD patients [20].
  • Increased expression of ND1 and COXI was also observed in nerve growth factor-differentiated PC12 cells undergoing apoptosis induced by tumor necrosis factor-alpha, suggesting that the differential regulation of certain mitochondrial mRNAs may be associated with this form of cell death [21].
  • NADPH-diaphorase reactivity was observed in three different classes of amacrine cells (ND1, ND2, ND3 cells) and in the cone photoreceptors [22].
  • We have confirmed an approximate 60% defect in mitochondrial NADH CoQ1 reductase activity in cultured fibroblasts bearing the 3460-bp G to A mutation within the ND1 gene [23].

Associations of MT-ND1 with chemical compounds

  • The primary mutation was identified as a homoplasmic transition at nucleotide 3460, which results in the substitution of threonine for alanine at position 52 of the ND1 protein [1].
  • This residue occurs within a very highly conserved hydrophilic loop, is invariantly alanine or glycine in all ND1 proteins, and is adjacent to an invariant aspartic acid residue [1].
  • This is in accordance with the proposal that the ND1 subunit interacts with rotenone and ubiquinone [24].
  • In one individual, we detected a T-to-C transition at position 1243 in the 12SrRNA, a change from threonine to alanine at position 67 of the ND1 protein, and from valine to isoleucine at position 197 of the ND2 protein [25].
  • This nucleotide alteration results in the substitution of proline for the highly conserved leucine residue at position 285 of the ND1 protein [16].

Regulatory relationships of MT-ND1

  • 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 [26].

Other interactions of MT-ND1

  • The mutations occur in the mtDNA genes coding for the ND1 and ND4 subunits of Complex I [24].
  • Four replacement mutations restricted only to LHON families were found, one in the ND1 gene at nt 4025, and three in the ND5 gene at nt 12,811, 13,637, and 13,967 [27].
  • After demethylation SRY gene expression was restored in PC3, ND-1, DU-145, TSUPr1 and DUPro [2].
  • Mitochondrial DNA regions in the cytochrome c oxidase subunit 1 (cox1) and NADH dehydrogenase subunit 1 (nad1) genes were amplified by PCR from total genomic DNA samples (n > 720) from Ascaris individuals from humans and pigs, and subjected to mutation scanning and subsequent selective sequencing [28].
  • Starting from a cohort of 50 NADH-oxidoreductase (complex I) deficient patients, we carried out the systematic sequence analysis of all mitochondrially encoded complex I subunits (ND1 to ND6 and ND4L) in affected tissues [29].

Analytical, diagnostic and therapeutic context of MT-ND1

  • By northern blot analysis, we demonstrated increased steady-state levels of RNA 19, a polycistronic transcript corresponding to the 16S rRNA + tRNA Leu(UUR) + ND1 genes (which are contiguous in the mtDNA) in heart, kidney, and muscle [30].
  • METHODS: Muscle samples of the medial rectus obtained from surgery in a sporadic case of CPEO associated with deleted mitochondrial DNA, and post mortem in a case of 3460/ND1 LHON were processed for electron microscopy (EM) [31].
  • Using specific ELISA kits, we investigated the secretion of cytokines in five human prostate carcinoma cell lines: ALVA 31, DU145, LNCaP, ND1 and PC3 [32].


  1. Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. Howell, N., Bindoff, L.A., McCullough, D.A., Kubacka, I., Poulton, J., Mackey, D., Taylor, L., Turnbull, D.M. Am. J. Hum. Genet. (1991) [Pubmed]
  2. DNA methylation regulates the expression of Y chromosome specific genes in prostate cancer. Dasari, V.K., Deng, D., Perinchery, G., Yeh, C.C., Dahiya, R. J. Urol. (2002) [Pubmed]
  3. A novel combination of mitochondrial tRNA and ND1 gene mutations in a syndrome with MELAS, cardiomyopathy, and diabetes mellitus. Jaksch, M., Hofmann, S., Kaufhold, P., Obermaier-Kusser, B., Zierz, S., Gerbitz, K.D. Hum. Mutat. (1996) [Pubmed]
  4. A heteroplasmic mitochondrial complex I gene mutation in adult-onset dystonia. Simon, D.K., Friedman, J., Breakefield, X.O., Jankovic, J., Brin, M.F., Provias, J., Bressman, S.B., Charness, M.E., Tarsy, D., Johns, D.R., Tarnopolsky, M.A. Neurogenetics (2003) [Pubmed]
  5. 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]
  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. Heteroplasmic mitochondrial DNA 3310 mutation in NADH dehydrogenase subunit 1 associated with type 2 diabetes, hypertrophic cardiomyopathy, and mental retardation in a single patient. Hattori, Y., Nakajima, K., Eizawa, T., Ehara, T., Koyama, M., Hirai, T., Fukuda, Y., Kinoshita, M. Diabetes Care (2003) [Pubmed]
  8. Mitochondrial DNA polymorphisms as risk factors for Parkinson's disease and Parkinson's disease dementia. Autere, J., Moilanen, J.S., Finnilä, S., Soininen, H., Mannermaa, A., Hartikainen, P., Hallikainen, M., Majamaa, K. Hum. Genet. (2004) [Pubmed]
  9. Trans splicing in Oenothera mitochondria: nad1 mRNAs are edited in exon and trans-splicing group II intron sequences. Wissinger, B., Schuster, W., Brennicke, A. Cell (1991) [Pubmed]
  10. URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit. Chomyn, A., Cleeter, M.W., Ragan, C.I., Riley, M., Doolittle, R.F., Attardi, G. Science (1986) [Pubmed]
  11. Multiple trans-splicing events are required to produce a mature nad1 transcript in a plant mitochondrion. Conklin, P.L., Wilson, R.K., Hanson, M.R. Genes Dev. (1991) [Pubmed]
  12. Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder. Hudson, G., Keers, S., Yu Wai Man, P., Griffiths, P., Huoponen, K., Savontaus, M.L., Nikoskelainen, E., Zeviani, M., Carrara, F., Horvath, R., Karcagi, V., Spruijt, L., de Coo, I.F., Smeets, H.J., Chinnery, P.F. Am. J. Hum. Genet. (2005) [Pubmed]
  13. Intragenic inversion of mtDNA: a new type of pathogenic mutation in a patient with mitochondrial myopathy. Musumeci, O., Andreu, A.L., Shanske, S., Bresolin, N., Comi, G.P., Rothstein, R., Schon, E.A., DiMauro, S. Am. J. Hum. Genet. (2000) [Pubmed]
  14. Mitochondrial complex I activity is significantly decreased in a patient with maternally inherited type 2 diabetes mellitus and hypertrophic cardiomyopathy associated with mitochondrial DNA C3310T mutation: A cybrid study. Chen, J., Hattori, Y., Nakajima, K., Eizawa, T., Ehara, T., Koyama, M., Hirai, T., Fukuda, Y., Kinoshita, M., Sugiyama, A., Hayashi, J., Onaya, T., Kobayashi, T., Tawata, M. Diabetes Res. Clin. Pract. (2006) [Pubmed]
  15. The complex I from Rhodobacter capsulatus. Dupuis, A., Chevallet, M., Darrouzet, E., Duborjal, H., Lunardi, J., Issartel, J.P. Biochim. Biophys. Acta (1998) [Pubmed]
  16. Leber hereditary optic neuropathy: involvement of the mitochondrial ND1 gene and evidence for an intragenic suppressor mutation. Howell, N., Kubacka, I., Xu, M., McCullough, D.A. Am. J. Hum. Genet. (1991) [Pubmed]
  17. Leber's hereditary optic neuropathy: biochemical effect of 11778/ND4 and 3460/ND1 mutations and correlation with the mitochondrial genotype. Carelli, V., Ghelli, A., Ratta, M., Bacchilega, E., Sangiorgi, S., Mancini, R., Leuzzi, V., Cortelli, P., Montagna, P., Lugaresi, E., Degli Esposti, M. Neurology (1997) [Pubmed]
  18. 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]
  19. Catalytic activity of complex I in cell lines that possess replacement mutations in the ND genes in Leber's hereditary optic neuropathy. Majander, A., Finel, M., Savontaus, M.L., Nikoskelainen, E., Wikström, M. Eur. J. Biochem. (1996) [Pubmed]
  20. Novel mitochondrial DNA mutations in Parkinson's disease. Richter, G., Sonnenschein, A., Grünewald, T., Reichmann, H., Janetzky, B. Journal of neural transmission (Vienna, Austria : 1996) (2002) [Pubmed]
  21. Is differential regulation of mitochondrial transcripts in Parkinson's disease related to apoptosis? Ruberg, M., Brugg, B., Prigent, A., Hirsch, E., Brice, A., Agid, Y. J. Neurochem. (1997) [Pubmed]
  22. NADPH-diaphorase neurones of human retinae have a uniform topographical distribution. Provis, J.M., Mitrofanis, J. Vis. Neurosci. (1990) [Pubmed]
  23. Functional consequences of the 3460-bp mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Cock, H.R., Cooper, J.M., Schapira, A.H. J. Neurol. Sci. (1999) [Pubmed]
  24. 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]
  25. Mitochondrial DNA mutations in patients with orthostatic hypotension. Schwartz, F., Baldwin, C.T., Baima, J., Gavras, H. Am. J. Med. Genet. (1999) [Pubmed]
  26. 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]
  27. The spectrum of mitochondrial DNA mutations in families with Leber hereditary optic neuroretinopathy. Huoponen, K., Lamminen, T., Juvonen, V., Aula, P., Nikoskelainen, E., Savontaus, M.L. Hum. Genet. (1993) [Pubmed]
  28. Mutation scanning-coupled analysis of haplotypic variability in mitochondrial DNA regions reveals low gene flow between human and porcine Ascaris in endemic regions of China. Peng, W., Yuan, K., Hu, M., Zhou, X., Gasser, R.B. Electrophoresis (2005) [Pubmed]
  29. Recurrent de novo mitochondrial DNA mutations in respiratory chain deficiency. Lebon, S., Chol, M., Benit, P., Mugnier, C., Chretien, D., Giurgea, I., Kern, I., Girardin, E., Hertz-Pannier, L., de Lonlay, P., Rötig, A., Rustin, P., Munnich, A. J. Med. Genet. (2003) [Pubmed]
  30. Mitochondrial DNA and RNA processing in MELAS. Kaufmann, P., Koga, Y., Shanske, S., Hirano, M., DiMauro, S., King, M.P., Schon, E.A. Ann. Neurol. (1996) [Pubmed]
  31. Human extraocular muscles in mitochondrial diseases: comparing chronic progressive external ophthalmoplegia with Leber's hereditary optic neuropathy. Carta, A., Carelli, V., D'Adda, T., Ross-Cisneros, F.N., Sadun, A.A. The British journal of ophthalmology. (2005) [Pubmed]
  32. Human prostate carcinoma cell lines secrete GM-CSF and express GM-CSF-receptor on their cell surface. Rokhlin, O.W., Griebling, T.L., Karassina, N.V., Raines, M.A., Cohen, M.B. Anticancer Res. (1996) [Pubmed]
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