MT-ND1

MT-ND1 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 1 (ND1) protein.[5] The ND1 protein is a subunit of NADH dehydrogenase, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.[6] Variants of the human MT-ND1 gene 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.[7][8][9]

ND1
Identifiers
AliasesND1, MTMT-NADH dehydrogenase, subunit 1 (complex I), NADH dehydrogenase subunit 1
External IDsOMIM: 516000 MGI: 101787 HomoloGene: 5011 GeneCards: ND1
Orthologs
SpeciesHumanMouse
Entrez

4535

17716

Ensembl

ENSG00000198888

ENSMUSG00000064341

UniProt

P03886

P03888

RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

NP_904328

Location (UCSC)Chr M: 0 – 0 MbChr M: 0 – 0 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Location of the MT-ND1 gene in the human mitochondrial genome. MT-ND1 is one of the seven NADH dehydrogenase mitochondrial genes (yellow boxes).

Structure

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 enzyme NADH dehydrogenase (ubiquinone), together with MT-ND2, 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-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]

Function

MT-ND1-encoded NADH-ubiquinone oxidoreductase chain 1 is a subunit of the respiratory chain Complex I that is supposed to belong to the minimal assembly of core proteins required to catalyze NADH dehydrogenation and electron transfer to ubiquinone (coenzyme Q10).[12] 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.[6]

Clinical significance

Pathogenic variants of the mitochondrial gene MT-ND1 are known to cause mtDNA-associated Leigh syndrome, as are variants of MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND2, 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 individuals 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-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] 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), overlap between LHON and MELAS,[13][14] and the previously mentioned Leigh syndrome.

Mitochondrial dysfunction resulting from variants of MT-ND1, MT-ND2 and MT-ND4L have been linked to BMI in adults and implicated in metabolic disorders including obesity, diabetes and hypertension.[9]

References

  1. GRCh38: Ensembl release 89: ENSG00000198888 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000064341 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: MT-ND1 NADH dehydrogenase subunit 1".
  6. Voet DJ, Voet JG, Pratt CW (2013). "Chapter 18, Mitochondrial ATP synthesis". Fundamentals of Biochemistry (4th ed.). Hoboken, NJ: Wiley. pp. 581–620. ISBN 978-0-47054784-7.
  7. Thorburn 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. PMID 20301352.
  8. 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 (May 2014). "Association of the mtDNA m.4171C>A/MT-ND1 mutation with both optic neuropathy and bilateral brainstem lesions". BMC Neurology. 14: 116. doi:10.1186/1471-2377-14-116. PMC 4047257. PMID 24884847.
  9. Flaquer A, Baumbach C, Kriebel J, Meitinger T, Peters A, Waldenberger M, Grallert H, Strauch K (2014). "Mitochondrial genetic variants identified to be associated with BMI in adults". PLOS ONE. 9 (8): e105116. Bibcode:2014PLoSO...9j5116F. doi:10.1371/journal.pone.0105116. PMC 4143221. PMID 25153900.
  10. 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 (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
  11. "NADH-ubiquinone oxidoreductase chain 1". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  12. "MT-ND1 - NADH-ubiquinone oxidoreductase chain 1 - Homo sapiens (Human)". UniProt.org: a hub for protein information. The UniProt Consortium.
  13. Spruijt L, Smeets HJ, Hendrickx A, Bettink-Remeijer MW, Maat-Kievit A, Schoonderwoerd KC, Sluiter W, de Coo IF, Hintzen RQ (June 2007). "A MELAS-associated ND1 mutation causing leber hereditary optic neuropathy and spastic dystonia". Archives of Neurology. 64 (6): 890–3. doi:10.1001/archneur.64.6.890. PMID 17562939.
  14. Blakely EL, de Silva R, King A, Schwarzer V, Harrower T, Dawidek G, Turnbull DM, Taylor RW (May 2005). "LHON/MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation". European Journal of Human Genetics. 13 (5): 623–7. doi:10.1038/sj.ejhg.5201363. PMID 15657614.

Further reading

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