Alternative titles; symbols
HGNC Approved Gene Symbol: MT-ND2
SNOMEDCT: 237988006, 58610003; ICD10CM: H47.22;
Subunit 2 of mitochondrial NADH dehydrogenase (Complex I) is 1 of 7 mitochondrial DNA (mtDNA) encoded subunits (MTND1, MTND2, MTND3, MTND4, MTND4L, MTND5, MTND6) included among the approximately 41 polypeptides of respiratory Complex I (NADH:ubiquinone oxidoreductase, EC 1.6.5.3) (Shoffner and Wallace, 1995; Arizmendi et al., 1992; Walker et al., 1992; Anderson et al., 1981; Attardi et al., 1986; Chomyn et al., 1985; Wallace et al., 1986; Oliver and Wallace, 1982; Wallace et al., 1994). Complex I accepts electrons from NADH, transfers them to ubiquinone (Coenzyme Q10), and uses the energy released to pump protons across the mitochondrial inner membrane. Complex I is more fully described under 516000. MTND2 is probably a component of the hydrophobic protein fragment of the complex (Ragan, 1987).
MTND2 is encoded by the guanine-rich heavy (H) strand of the mtDNA and located between nucleotide pairs (nps) 4470 and 5511 (Anderson et al., 1981; Wallace et al., 1994). It is maternally inherited along with the mtDNA (Giles et al., 1980; Case and Wallace, 1981).
The MTND2 gene encompasses 1041 nps of continuous coding sequence. It contains no introns, begins with the ATT start codon and ends with the U of the UAA stop codon (Anderson et al., 1981; Ojala et al., 1981; Montoya et al., 1981). It is transcribed as part of the polycistronic H-strand transcript, flanked by tRNA(Met) and tRNA(Trp) RNAs. The tRNAs are cleaved out freeing transcript 12, the MTND2 mRNA. The mRNA is then polyadenylated completing the termination codon (Anderson et al., 1981; Ojala et al., 1981; Attardi et al., 1982).
The predicted polypeptide has a molecular weight of 38.9 kD (Anderson et al., 1981; Wallace et al., 1994). However, its apparent MW on SDS-polyacrylamide gels (PAGE) using Tris-glycine buffer is 31.5 kD, whereas the apparent MW using urea-phosphate buffer is 25 kD (Oliver et al., 1984; Oliver and Wallace, 1982; Wallace et al., 1986; Chomyn et al. (1985, 1986); Wallace et al., 1994).
Restriction site polymorphisms have been identified at the following nucleotide position for the indicated enzymes (where '+'= site gain, '-'= site loss relative to the reference sequence, Anderson et al., 1981): Alu I: -4631, -4685, -4769, +4877, -4990, -5176; Ava II: +4481/10933, +5259; Dde I: -5003, +5076; Hae II: +4830; Hae III: -4563, +4793, -4848, -5261, +5315; Hha I: +4831, +5351; HinfI: +4546, -4810, +5072, +5198; Mbo: +5372, +5389; Msp I: +4593, -4711; Rsa I: +4643, +4723, +4732/4735, +4745, -5054, +5164, +5492; Taq I: +5125, -5269, +5370 (Wallace et al., 1994).
Allelic variants for MTND2 have been associated with Leber hereditary optic neuropathy (LHON; 535000); see, for example, MTND2*LHON4917G (516001.0001) and MTND2*LHON5244A (516001.0002).
Tanaka et al. (1998) analyzed the MTND2 5178 adenine/cytosine (5178A/C) polymorphism and reported that 5178A may be associated with longevity. This substitution results in an amino acid change of methionine to leucine at residue 237. Kokaze et al. (2001) reported an association of the 5178A/C polymorphism with serum lipid levels in Japanese. High density lipoprotein cholesterol in males carrying 5178A was significantly higher than in males carrying 5178C. Triglyceride (TG) concentration in females carrying 5178A was significantly lower than in females carrying 5178C. This difference in TG levels between the 2 genotypes was more evident in postmenopausal females than in premenopausal females. An antiatherogenic effect of 5178A seemed to be indicated.
In a study in Yunan Province, China, Yao et al. (2002) failed to find an association between mtDNA 5178A (or haplogroup D) and longevity.
This allele converts the highly conserved aspartate at amino acid 150 to an asparagine. It is commonly associated with the MTND1*LHON4216 allele in patients with LHON (535000), but is also found in 3% of the general population. Hence, its pathogenic significance is uncertain. 4917 (Johns and Berman, 1991).
This allele changes a highly conserved glycine at amino acid 259 to a serine. The mutation was found in an LHON (535000) patient who also harbored the MTND6*LHON14484A, MTCYB*LHON15257A, MTND5*LHON13708A, and MTCYB*LHON15812A alleles. The mutation was heteroplasmic and probably contributed to the pathogenesis of this mtDNA (Brown et al., 1992).
In a family with LHON (535000) in Russia, Brown et al. (2001) found a C-to-A transversion at nucleotide 4640 of the MTND2 gene, representing a novel missense mutation. The 4640A mutation replaced a poorly conserved isoleucine with a methionine at MTND2 amino acid 57. Mutation-specific restriction enzyme analysis revealed that the mutation was homoplasmic.
Mammalian mitochondrial DNA is thought to be strictly maternally inherited. Sperm mitochondria disappear in early embryogenesis by selective destruction, inactivation, or simple dilution by the vast surplus of oocyte mitochondria. Very small amounts of paternally inherited mtDNA have been detected by PCR in mice after several generations of interspecific backcrosses Gyllensten et al. (1991). Studies of such hybrids and of mouse oocytes microinjected with sperm support the hypothesis that sperm mitochondria are targeted for destruction by nuclear-encoded proteins (Cummins et al., 1998; Shitara et al. (1998, 2000)). Schwartz and Vissing (2002) reported the case of a 28-year-old man with mitochondrial myopathy due to a 2-bp deletion in the MTND2 gene removing 2 adenines from the AAA triplet at nucleotides 5132 to 5134. They determined that the mtDNA harboring the mutation was paternal in origin and accounted for 90% of the patient's muscle mtDNA. The haplotype of the mitochondrial chromosome carrying the 2-bp deletion was clearly that of the father; the mother and the unaffected sister had a different haplotype. The patient had severe, lifelong exercise intolerance, and had never been able to run more than a few steps. Cardiac and pulmonary functions were normal, and he was otherwise well. Both parents and a 23-year-old sister were healthy and had normal exercise tolerance. The myopathic symptoms were associated with severe lactic acidosis induced by minor physical exertion. Biopsies of the right and left quadriceps muscle revealed that 15% of fibers were of the ragged-red type. Biochemical analysis demonstrated an isolated deficiency of mitochondrial enzyme complex I (252010) of the respiratory chain in muscle. There were no signs of muscular atrophy.
Pulkes et al. (2005) described a 49-year-old woman who had experienced exercise intolerance since the first decade of her life. She was unable to engage in sports at school and always had great difficulty with repetitive motor tasks of daily life because of fatigue and myalgia. Chronic fatigue syndrome had been diagnosed. There was mild thoracic kyphoscoliosis, bilateral mild ptosis, and mild early external ophthalmoplegia. There was also mild weakness of her neck flexion and symmetric proximal limb weakness. Repetitive testing caused rapid power fatigue. At age 49, she could walk only about 50 meters before experiencing fatigue and myalgia. Biochemical analysis showed complex I deficiency (252010). Pulkes et al. (2005) identified a novel heteroplasmic nonsense mutation in the MTND2 gene: a 4810G-A transition causing a change in tryptophan to a stop codon at position 114. This change predicted a truncated ND2 protein with a loss of 233 amino acids from the C terminus. The mutation was heteroplasmic in muscle and absent from blood. Single-fiber PCR analysis revealed a positive correlation between the proportion of mutant mtDNA and abnormal muscle fiber morphology.
In fibroblasts from a patient with Leigh syndrome due to mitochondrial complex I deficiency (256000), Hinttala et al. (2006) identified a heteroplasmic 4681T-C transition in the MTND2 gene, resulting in a leu71-to-pro (L71P) substitution in the third transmembrane helix of the ND2 subunit. The patient had progressive encephalomyopathy and died from respiratory failure at age 10 years.
Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., Schreier, P. H., Smith, A. J. H., Staden, R., Young, I. G. Sequence and organization of the human mitochondrial genome. Nature 290: 457-465, 1981. [PubMed: 7219534] [Full Text: https://doi.org/10.1038/290457a0]
Arizmendi, J. M., Skehel, J. M., Runswick, M. J., Fearnley, I. M., Walker, J. E. Complementary DNA sequences of two 14.5 kDa subunits of NADH:ubiquinone oxidoreductase from bovine heart mitochondria. Complementation of the primary structure of the complex FEBS Lett. 313: 80-84, 1992. [PubMed: 1426273] [Full Text: https://doi.org/10.1016/0014-5793(92)81189-s]
Attardi, G., Chomyn, A., Doolittle, R. F., Mariottini, P., Ragan, C. I. Seven unidentified reading frames of human mitochondrial DNA encode subunits of the respiratory chain NADH dehydrogenase. Cold Spring Harbor Symp. Quant. Biol. 51: 103-114, 1986. [PubMed: 3472707] [Full Text: https://doi.org/10.1101/sqb.1986.051.01.013]
Attardi, G., Chomyn, A., Montoya, J., Ojala, D. Identification and mapping of human mitochondrial genes. Cytogenet. Cell Genet. 32: 85-98, 1982. [PubMed: 7140372] [Full Text: https://doi.org/10.1159/000131689]
Brown, M. D., Voljavec, A. S., Lott, M. T., Torroni, A., Yang, C.-C., Wallace, D. C. Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy. Genetics 130: 163-173, 1992. [PubMed: 1732158] [Full Text: https://doi.org/10.1093/genetics/130.1.163]
Brown, M. D., Zhadanov, S., Allen, J. C., Hosseini, S., Newman, N. J., Atamonov, V. V., Mikhailovskaya, I. E., Sukernik, R. I., Wallace, D. C. Novel mtDNA mutations and oxidative phosphorylation dysfunction in Russian LHON families. Hum. Genet. 109: 33-39, 2001. [PubMed: 11479733] [Full Text: https://doi.org/10.1007/s004390100538]
Case, J. T., Wallace, D. C. Maternal inheritance of mitochondrial DNA polymorphisms in cultured human fibroblasts. Somat. Cell Genet. 7: 103-108, 1981. [PubMed: 6261411] [Full Text: https://doi.org/10.1007/BF01544751]
Chomyn, A., Cleeter, W. J., Ragan, C. I., Riley, M., Doolittle, R. F., Attardi, G. URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit. Science 234: 614-618, 1986. [PubMed: 3764430] [Full Text: https://doi.org/10.1126/science.3764430]
Chomyn, A., Mariottini, P., Cleeter, M. W. J., Ragan, C. I., Matsuno-Yagi, A., Hatefi, Y., Doolittle, R. G., Attardi, G. Six unidentified reading frames of human mitochondrial DNA encode components of the respiratory-chain NADH dehydrogenase. Nature 314: 592-597, 1985. [PubMed: 3921850] [Full Text: https://doi.org/10.1038/314592a0]
Cummins, J. M., Wakayama, T., Yanagimachi, R. Fate of microinjected spermatid mitochondria in the mouse oocyte and embryo. Zygote 6: 213-222, 1998. [PubMed: 9854792] [Full Text: https://doi.org/10.1017/s0967199498000148]
Giles, R. E., Blanc, H., Cann, H. M., Wallace, D. C. Maternal inheritance of human mitochondrial DNA. Proc. Nat. Acad. Sci. 77: 6715-6719, 1980. [PubMed: 6256757] [Full Text: https://doi.org/10.1073/pnas.77.11.6715]
Gyllensten, U., Wharton, D., Josefsson, A., Wilson, A. C. Paternal inheritance of mitochondrial DNA in mice. Nature 352: 255-257, 1991. [PubMed: 1857422] [Full Text: https://doi.org/10.1038/352255a0]
Hinttala, R., Smeets, R., Moilanen, J. S., Ugalde, C., Uusimaa, J., Smeitink, J. A. M., Majamaa, K. Analysis of mitochondrial DNA sequences in patients with isolated or combined oxidative phosphorylation system deficiency. (Letter) J. Med. Genet. 43: 881-886, 2006. [PubMed: 16738010] [Full Text: https://doi.org/10.1136/jmg.2006.042168]
Johns, D. R., Berman, J. Alternative, simultaneous complex I mitochondrial DNA mutations in Leber's hereditary optic atrophy. Biochem. Biophys. Res. Commun. 174: 1324-1330, 1991. [PubMed: 1900003] [Full Text: https://doi.org/10.1016/0006-291x(91)91567-v]
Kokaze, A., Ishikawa, M., Matsunaga, N., Yoshida, M., Sekine, Y., Teruya, K., Takeda, N., Sumiya, Y., Uchida, Y., Takashima, Y. Association of the mitochondrial DNA 5178 A/C polymorphism with serum lipid levels in the Japanese population. Hum. Genet. 109: 521-525, 2001. [PubMed: 11735027] [Full Text: https://doi.org/10.1007/s004390100602]
Montoya, J., Ojala, D., Attardi, G. Distinctive features of the 5-prime terminal sequences of the human mitochondrial mRNAs. Nature 290: 465-470, 1981. [PubMed: 7219535] [Full Text: https://doi.org/10.1038/290465a0]
Ojala, D., Montoya, J., Attardi, G. tRNA punctuation model of RNA processing in human mitochondria. Nature 290: 470-474, 1981. [PubMed: 7219536] [Full Text: https://doi.org/10.1038/290470a0]
Oliver, N. A., McCarthy, J., Wallace, D. C. Comparison of mitochondrially synthesized polypeptides of human, mouse, and monkey cell lines by a two-dimensional protease gel system. Somat. Cell Molec. Genet. 10: 639-643, 1984. [PubMed: 6438810] [Full Text: https://doi.org/10.1007/BF01535230]
Oliver, N. A., Wallace, D. C. Assignment of two mitochondrially synthesized polypeptides to human mitochondrial DNA and their use in the study of intracellular mitochondrial interaction. Molec. Cell. Biol. 2: 30-41, 1982. [PubMed: 6955589] [Full Text: https://doi.org/10.1128/mcb.2.1.30-41.1982]
Pulkes, T., Liolitsa, D., Wills, A. J., Hargreaves, I., Heales, S., Hanna, M. G. Nonsense mutations in mitochondrial DNA associated with myalgia and exercise intolerance. Neurology 64: 1091-1092, 2005. [PubMed: 15781840] [Full Text: https://doi.org/10.1212/01.WNL.0000154471.33156.55]
Ragan, C. I. Structure of NADH-ubiquinone reductase (Complex I). Curr. Top. Bioenerg. 15: 1-36, 1987.
Schwartz, M., Vissing, J. Paternal inheritance of mitochondrial DNA. New Eng. J. Med. 347: 576-580, 2002. [PubMed: 12192017] [Full Text: https://doi.org/10.1056/NEJMoa020350]
Shitara, H., Hayashi, J.-I., Takahama, S., Kaneda, H., Yonekawa, H. Maternal inheritance of mouse mtDNA in interspecific hybrids: segregation of the leaked paternal mtDNA followed by the prevention of subsequent paternal leakage. Genetics 148: 851-858, 1998. [PubMed: 9504930] [Full Text: https://doi.org/10.1093/genetics/148.2.851]
Shitara, H., Kaneda, H., Sato, A., Inoue, K., Ogura, A., Yonekawa, H., Hayashi, J.-I. Selective and continuous elimination of mitochondria microinjected into mouse eggs from spermatids, but not from liver cells, occurs throughout embryogenesis. Genetics 156: 1277-1284, 2000. [PubMed: 11063701] [Full Text: https://doi.org/10.1093/genetics/156.3.1277]
Shoffner, J. M., Wallace, D. C. Oxidative phosphorylation diseases.In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.) : The Metabolic and Molecular Bases of Inherited Disease. Vol. 1. (7th ed.) New York: McGraw-Hill (pub.) 1995. Pp. 1535-1609.
Tanaka, M., Gong, J.-S., Zhang, J., Yoneda, M., Yagi, K. Mitochondrial genotype associated with longevity. (Letter) Lancet 351: 185-186, 1998. [PubMed: 9449878] [Full Text: https://doi.org/10.1016/S0140-6736(05)78211-8]
Walker, J. E., Arizmendi, J. M., Dupuis, A., Fearnley, I. M., Finel, M., Medd, S. M., Pilkington, S. J., Runswick, M. J., Skehel, J. M. Sequences of 20 subunits of NADH:ubiquinone oxidoreductase from bovine heart mitochondria: application of a novel strategy for sequencing proteins using the polymerase chain reaction. J. Molec. Biol. 226: 1051-1072, 1992. [PubMed: 1518044] [Full Text: https://doi.org/10.1016/0022-2836(92)91052-q]
Wallace, D. C., Lott, M. T., Torroni, A., Brown, M. D., Shoffner, J. M. Report of the committee on human mitochondrial DNA.In: Cuticchia, A. J.; Pearson, P. (eds.) : Human Gene Mapping, 1993: A Compendium. Baltimore: Johns Hopkins Univ. Press (pub.) 1994. Pp. 813-845.
Wallace, D. C., Yang, J., Ye, J., Lott, M. T., Oliver, N. A., McCarthy, J. Computer prediction of peptide maps: Assignment of polypeptides to human and mouse mitochondrial DNA genes by analysis of two-dimensional-proteolytic digest gels. Am. J. Hum. Genet. 38: 461-481, 1986. [PubMed: 3518425]
Yao, Y.-G., Kong, Q.-P., Zhang, Y.-P. Mitochondrial DNA 5178A polymorphism and longevity. Hum. Genet. 111: 462-463, 2002. [PubMed: 12384792] [Full Text: https://doi.org/10.1007/s00439-002-0826-z]