MT-ND1 is located in mitochondrial DNA from base pair 3,307 to 4,262.[5] The MT-ND1 gene produces a 36 kDa protein composed of 318 amino acids.[10][11] MT-ND1 is one of seven mitochondrial genes encoding subunits of the enzymeNADH dehydrogenase (ubiquinone), together withMT-ND2,MT-ND3,MT-ND4,MT-ND4L,MT-ND5, andMT-ND6. Also known asComplex I, this enzyme is the largest of the respiratory complexes. The structure is L-shaped with a long,hydrophobictransmembrane domain and ahydrophilic domain for the peripheral arm that includes all the known redox centres and the NADH binding site. The MT-ND1 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.[6]
MT-ND1-encoded NADH-ubiquinone oxidoreductase chain 1 is a subunit of the respiratory chainComplex I that is supposed to belong to the minimal assembly of core proteins required to catalyzeNADH dehydrogenation andelectron transfer toubiquinone (coenzyme Q10).[12] Initially,NADH binds to Complex I and transfers two electrons to theisoalloxazine ring of theflavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series ofiron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced toubiquinol (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.[6]
Pathogenic variants of the mitochondrial gene MT-ND1 are known to cause mtDNA-associatedLeigh syndrome, as are variants ofMT-ATP6,MT-TL1,MT-TK,MT-TW,MT-TV,MT-ND2,MT-ND3,MT-ND4,MT-ND5,MT-ND6 andMT-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 individuals die of respiratory or cardiac failure by the age of three.Leigh syndrome is a maternally inherited disorder and its diagnosis is established throughgenetic testing of the aforementioned mitochondrial genes, including MT-ND1.[7] The m.4171C>A/MT-ND1 mutation also leads to a Leigh-like phenotype as well as bilateral brainstem lesions affecting the vestibular nuclei, resulting in vision loss, vomiting and vertigo.[8] Thesecomplex I genes have been associated with a variety of neurodegenerative disorders, includingLeber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS), overlap between LHON and MELAS,[13][14] and the previously mentionedLeigh syndrome.
Mitochondrial dysfunction resulting from variants of MT-ND1,MT-ND2 andMT-ND4L have been linked to BMI in adults and implicated in metabolic disorders including obesity, diabetes and hypertension.[9]
^abcVoet DJ, Voet JG, Pratt CW (2013). "Chapter 18, Mitochondrial ATP synthesis".Fundamentals of Biochemistry (4th ed.). Hoboken, NJ: Wiley. pp. 581–620.ISBN978-0-47054784-7.
^abThorburn DR, Rahman S (1993–2015)."Mitochondrial DNA-Associated Leigh Syndrome and NARP". In Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Dolan CR, Fong CT, Smith RJ, Stephens K (eds.).GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle.PMID20301352.
Torroni A, Achilli A, Macaulay V, Richards M, Bandelt HJ (June 2006). "Harvesting the fruit of the human mtDNA tree".Trends in Genetics.22 (6):339–45.doi:10.1016/j.tig.2006.04.001.PMID16678300.
Bodenteich A, Mitchell LG, Polymeropoulos MH, Merril CR (May 1992). "Dinucleotide repeat in the human mitochondrial D-loop".Human Molecular Genetics.1 (2): 140.doi:10.1093/hmg/1.2.140-a.PMID1301157.
Lu X, Walker T, MacManus JP, Seligy VL (July 1992). "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.PMID1377597.
Marzuki S, Noer AS, Lertrit P, Thyagarajan D, Kapsa R, Utthanaphol P, Byrne E (December 1991). "Normal variants of human mitochondrial DNA and translation products: the building of a reference data base".Human Genetics.88 (2):139–45.doi:10.1007/bf00206061.PMID1757091.S2CID28048453.
Attardi G, Chomyn A, Doolittle RF, Mariottini P, Ragan CI (1987). "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.doi:10.1101/sqb.1986.051.01.013.PMID3472707.
Chomyn A, Cleeter MW, Ragan CI, Riley M, Doolittle RF, Attardi G (October 1986). "URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit".Science.234 (4776):614–8.Bibcode:1986Sci...234..614C.doi:10.1126/science.3764430.PMID3764430.
Chomyn A, Mariottini P, Cleeter MW, Ragan CI, Matsuno-Yagi A, Hatefi Y, Doolittle RF, Attardi G (1985). "Six unidentified reading frames of human mitochondrial DNA encode components of the respiratory-chain NADH dehydrogenase".Nature.314 (6012):592–7.Bibcode:1985Natur.314..592C.doi:10.1038/314592a0.PMID3921850.S2CID32964006.
Sanger F, Coulson AR, Barrell BG, Smith AJ, Roe BA (October 1980). "Cloning in single-stranded bacteriophage as an aid to rapid DNA sequencing".Journal of Molecular Biology.143 (2):161–78.doi:10.1016/0022-2836(80)90196-5.PMID6260957.
Pagani S, Galante YM (January 1983). "Interaction of rhodanese with mitochondrial NADH dehydrogenase".Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology.742 (2):278–84.doi:10.1016/0167-4838(83)90312-6.PMID6402020.
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 (April 1981). "Sequence and organization of the human mitochondrial genome".Nature.290 (5806):457–65.Bibcode:1981Natur.290..457A.doi:10.1038/290457a0.PMID7219534.S2CID4355527.
Nakagawa Y, Ikegami H, Yamato E, Takekawa K, Fujisawa T, Hamada Y, Ueda H, Uchigata Y, Miki T, Kumahara Y (April 1995). "A new mitochondrial DNA mutation associated with non-insulin-dependent diabetes mellitus".Biochemical and Biophysical Research Communications.209 (2):664–8.Bibcode:1995BBRC..209..664N.doi:10.1006/bbrc.1995.1550.PMID7733935.
