MT-ND2 explained

MT-ND2 is a gene of the mitochondrial genome coding for the NADH dehydrogenase 2 (ND2) protein.^[1] The ND2 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] Variants of human MT-ND2 are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh's syndrome (LS), Leber's hereditary optic neuropathy (LHON) and increases in adult BMI.^{[3] [4] [5]}

Structure

MT-ND2 is located in mitochondrial DNA from base pair 4,470 to 5,511. The MT-ND2 gene produces a 39 kDa protein composed of 347 amino acids.^{[6] [7]} MT-ND2 is one of seven mitochondrial genes encoding subunits of the enzyme NADH dehydrogenase (ubiquinone), together with MT-ND1, MT-ND3, MT-ND4, MT-ND4L, MT-ND5, and MT-ND6. Also known as Complex I, this enzyme 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. The MT-ND2 product 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]

Function

The MT-ND2 product 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).^[8] 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]

Clinical significance

Pathogenic variants of the mitochondrial gene MT-ND2 are known to cause mtDNA-associated Leigh syndrome, as are variants of MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND3, MT-ND4, MT-ND5, MT-ND6 and MT-CO3. Abnormalities in mitochondrial energy generation result in neurodegenerative disorders like Leigh syndrome, which is characterized by an onset of symptoms between 12 months and three years of age. The symptoms frequently present themselves following a viral infection and include movement disorders and peripheral neuropathy, as well as hypotonia, spasticity and cerebellar ataxia. Roughly half of affected patients die of respiratory or cardiac failure by the age of three. Leigh syndrome is a maternally inherited disorder and its diagnosis is established through genetic testing of the aforementioned mitochondrial genes, including MT-ND2. These complex I genes have been associated with a variety of neurodegenerative disorders, including Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS) and the previously mentioned Leigh syndrome.

Mitochondrial dysfunction resulting from variants of MT-ND2, MT-ND1 and MT-ND4L have been linked to BMI in adults and implicated in metabolic disorders including obesity, diabetes and hypertension.

Further reading

• Torroni A, Achilli A, Macaulay V, Richards M, Bandelt HJ . Harvesting the fruit of the human mtDNA tree . Trends in Genetics . 22 . 6 . 339–45 . Jun 2006 . 16678300 . 10.1016/j.tig.2006.04.001 .
• Bodenteich A, Mitchell LG, Polymeropoulos MH, Merril CR . Dinucleotide repeat in the human mitochondrial D-loop . Human Molecular Genetics . 1 . 2 . 140 . May 1992 . 1301157 . 10.1093/hmg/1.2.140-a . free .
• Lin FH, Lin R, Wisniewski HM, Hwang YW, Grundke-Iqbal I, Healy-Louie G, Iqbal K . Detection of point mutations in codon 331 of mitochondrial NADH dehydrogenase subunit 2 in Alzheimer's brains . Biochemical and Biophysical Research Communications . 182 . 1 . 238–46 . Jan 1992 . 1370613 . 10.1016/S0006-291X(05)80136-6 .
• Lu X, Walker T, MacManus JP, Seligy VL . Differentiation of HT-29 human colonic adenocarcinoma cells correlates with increased expression of mitochondrial RNA: effects of trehalose on cell growth and maturation . Cancer Research . 52 . 13 . 3718–25 . Jul 1992 . 1377597 .
• Brown MD, Voljavec AS, Lott MT, Torroni A, Yang CC, Wallace DC . Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy . Genetics . 130 . 1 . 163–73 . Jan 1992 . 10.1093/genetics/130.1.163 . 1732158 . 1204789 .
• Marzuki S, Noer AS, Lertrit P, Thyagarajan D, Kapsa R, Utthanaphol P, Byrne E . Normal variants of human mitochondrial DNA and translation products: the building of a reference data base . Human Genetics . 88 . 2 . 139–45 . Dec 1991 . 1757091 . 10.1007/bf00206061 . 28048453 .
• Johns DR, Berman J . Alternative, simultaneous complex I mitochondrial DNA mutations in Leber's hereditary optic neuropathy . Biochemical and Biophysical Research Communications . 174 . 3 . 1324–30 . Feb 1991 . 1900003 . 10.1016/0006-291X(91)91567-V . free .
• Moraes CT, Andreetta F, Bonilla E, Shanske S, DiMauro S, Schon EA . Replication-competent human mitochondrial DNA lacking the heavy-strand promoter region . Molecular and Cellular Biology . 11 . 3 . 1631–7 . Mar 1991 . 1996112 . 369459 . 10.1128/MCB.11.3.1631.
• Attardi G, Chomyn A, Doolittle RF, Mariottini P, Ragan CI . Seven unidentified reading frames of human mitochondrial DNA encode subunits of the respiratory chain NADH dehydrogenase . Cold Spring Harbor Symposia on Quantitative Biology . 51 . 1. 103–14 . 1987 . 3472707 . 10.1101/sqb.1986.051.01.013 .
• Chomyn A, Cleeter MW, Ragan CI, Riley M, Doolittle RF, Attardi G . URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit . Science . 234 . 4776 . 614–8 . Oct 1986 . 3764430 . 10.1126/science.3764430 . 1986Sci...234..614C .
• Chomyn A, Mariottini P, Cleeter MW, Ragan CI, Matsuno-Yagi A, Hatefi Y, Doolittle RF, Attardi G . Six unidentified reading frames of human mitochondrial DNA encode components of the respiratory-chain NADH dehydrogenase . Nature . 314 . 6012 . 592–7 . 1985 . 3921850 . 10.1038/314592a0 . 1985Natur.314..592C . 32964006 .
• Sanger F, Coulson AR, Barrell BG, Smith AJ, Roe BA . Cloning in single-stranded bacteriophage as an aid to rapid DNA sequencing . Journal of Molecular Biology . 143 . 2 . 161–78 . Oct 1980 . 6260957 . 10.1016/0022-2836(80)90196-5 .
• Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG . Sequence and organization of the human mitochondrial genome . Nature . 290 . 5806 . 457–65 . Apr 1981 . 7219534 . 10.1038/290457a0 . 1981Natur.290..457A . 4355527 .
• Montoya J, Ojala D, Attardi G . Distinctive features of the 5'-terminal sequences of the human mitochondrial mRNAs . Nature . 290 . 5806 . 465–70 . Apr 1981 . 7219535 . 10.1038/290465a0 . 1981Natur.290..465M . 4358928 .
• Horai S, Hayasaka K, Kondo R, Tsugane K, Takahata N . Recent African origin of modern humans revealed by complete sequences of hominoid mitochondrial DNAs . Proceedings of the National Academy of Sciences of the United States of America . 92 . 2 . 532–6 . Jan 1995 . 7530363 . 42775 . 10.1073/pnas.92.2.532 . 1995PNAS...92..532H . free .
• Rieder MJ, Taylor SL, Tobe VO, Nickerson DA . Automating the identification of DNA variations using quality-based fluorescence re-sequencing: analysis of the human mitochondrial genome . Nucleic Acids Research . 26 . 4 . 967–73 . Feb 1998 . 9461455 . 147367 . 10.1093/nar/26.4.967 .
• Wise CA, Sraml M, Easteal S . Departure from neutrality at the mitochondrial NADH dehydrogenase subunit 2 gene in humans, but not in chimpanzees . Genetics . 148 . 1 . 409–21 . Jan 1998 . 10.1093/genetics/148.1.409 . 9475751 . 1459762 .
• Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N . Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA . Nature Genetics . 23 . 2 . 147 . Oct 1999 . 10508508 . 10.1038/13779 . 32212178 . free .
• Ingman M, Kaessmann H, Pääbo S, Gyllensten U . Mitochondrial genome variation and the origin of modern humans . Nature . 408 . 6813 . 708–13 . Dec 2000 . 11130070 . 10.1038/35047064 . 2000Natur.408..708I . 52850476 .
• Finnilä S, Lehtonen MS, Majamaa K . Phylogenetic network for European mtDNA . American Journal of Human Genetics . 68 . 6 . 1475–84 . Jun 2001 . 11349229 . 1226134 . 10.1086/320591 .

External links

• Mass spectrometry characterization of MT-ND2 at COPaKB

Notes and References

1. Web site: Entrez Gene: MT-ND2 NADH dehydrogenase subunit 2.
2. Book: Fundamentals of Biochemistry . Chapter 18: Mitochondrial ATP synthesis . Donald J. . Voet . Judith G. . Voet . Charlotte W. . Pratt . Wiley . Hoboken, NJ . 2013 . 978-0-47054784-7 . 581–620 . 4th . vanc .
3. Book: GeneReviews [Internet] . Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Dolan CR, Fong CT, Smith RJ, Stephens K . Thorburn DR, Rahman S . Mitochondrial DNA-Associated Leigh Syndrome and NARP . https://www.ncbi.nlm.nih.gov/books/NBK1173 . University of Washington, Seattle . Seattle (WA) . 1993–2015 . 20301352 .
4. La Morgia C, Caporali L, Gandini F, Olivieri A, Toni F, Nassetti S, Brunetto D, Stipa C, Scaduto C, Parmeggiani A, Tonon C, Lodi R, Torroni A, Carelli V . Association of the mtDNA m.4171C>A/MT-ND1 mutation with both optic neuropathy and bilateral brainstem lesions . BMC Neurology . 14 . 116 . 2014 . 24884847 . 4047257 . 10.1186/1471-2377-14-116 . free .
5. Flaquer A, Baumbach C, Kriebel J, Meitinger T, Peters A, Waldenberger M, Grallert H, Strauch K . Mitochondrial genetic variants identified to be associated with BMI in adults . PLOS ONE . 9 . 8 . e105116 . 2014 . 25153900 . 4143221 . 10.1371/journal.pone.0105116 . 2014PLoSO...9j5116F . free .
6. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–53 . Oct 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
7. Web site: Mitochondrially encoded NADH dehydrogenase 2 . Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) .
8. Web site: MT-ND2 - NADH-ubiquinone oxidoreductase chain 2 - Homo sapiens (Human). UniProt.org: a hub for protein information. The UniProt Consortium.