MT-ND1

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NADH dehydrogenase, subunit 1 (complex I)
Identifiers
Symbols ND1 ; MTND1
External IDs OMIM516000 MGI101787 HomoloGene5011 ChEMBL: 2111 GeneCards: ND1 Gene
Orthologs
Species Human Mouse
Entrez 4535 17716
Ensembl ENSG00000198888 ENSMUSG00000064341
UniProt P03886 P03888
RefSeq (mRNA) n/a n/a
RefSeq (protein) n/a NP_904328
Location (UCSC) Chr MT:
0 – 0 Mb
Chr MT:
0 – 0 Mb
PubMed search [1] [2]

NADH-ubiquinone oxidoreductase chain 1 is a protein that in humans is encoded by the mitochondrial gene MT-ND1.[1] The ND1 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 the 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.[3][4][5]

Structure[edit]

MT-ND1 is located in mitochondrial DNA from base pair 3,307 to 4,262.[1] The MT-ND1 gene produces a 36 kDa protein composed of 318 amino acids.[6][7] MT-ND1 is one of seven mitochondrially-encoded subunits of the enzyme NADH dehydrogenase (ubiquinone). Also known as Complex I, it 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. MT-ND1 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[edit]

MT-ND1 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[edit]

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 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-ND1.[3] The m.4171C>A/MT-ND1 mutation also leads to a Leigh-type phenotype as well as bilateral brainstem lesions affecting the vestibular nuclei, resulting in vision loss, vomiting and vertigo. 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.[4]

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.[5]

References[edit]

  1. ^ a b "Entrez Gene: MT-ND1 NADH dehydrogenase subunit 1". 
  2. ^ a b c 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. 
  3. ^ a b 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. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle. 
  4. ^ a b 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. doi:10.1186/1471-2377-14-116. PMID 24884847. 
  5. ^ a b 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). doi:10.1371/journal.pone.0105116. PMID 25153900. 
  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 (Oct 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. 
  7. ^ "NADH-ubiquinone oxidoreductase chain 1". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). 
  8. ^ "MT-ND1 - NADH-ubiquinone oxidoreductase chain 1 - Homo sapiens (Human)". UniProt.org: a hub for protein information. The UniProt Consortium. 

Further reading[edit]

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