MT-ND4L
| NADH dehydrogenase, subunit 4L (complex I) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||||||
| Symbols | ND4L ; MTND4L | ||||||||||||
| External IDs | OMIM: 516004 MGI: 102497 HomoloGene: 5021 ChEMBL: 2091 GeneCards: ND4L Gene | ||||||||||||
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| Orthologs | |||||||||||||
| Species | Human | Mouse | |||||||||||
| Entrez | 4539 | 17720 | |||||||||||
| Ensembl | ENSG00000212907 | ENSMUSG00000065947 | |||||||||||
| UniProt | P03901 | P03903 | |||||||||||
| RefSeq (mRNA) | n/a | n/a | |||||||||||
| RefSeq (protein) | n/a | NP_904336 | |||||||||||
| Location (UCSC) |
Chr MT: 0.01 – 0.01 Mb |
Chr MT: 0.01 – 0.01 Mb | |||||||||||
| PubMed search | |||||||||||||
NADH-ubiquinone oxidoreductase chain 4L is a protein that in humans is encoded by the mitochondrial gene MT-ND4L.[1] The ND4L 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 MT-ND4L are associated with increased BMI in adults and Leber's Hereditary Optic Neuropathy (LHON).[3][4]
Structure
The MT-ND4L gene is located in human mitochondrial DNA from base pair 10,469 to 10,765.[1][5] An unusual feature of the human MT-ND4L gene is the 7-nucleotide gene overlap of its last three codons (5'-CAA TGC TAA-3' coding for Gln, Cys and Stop) with the first three codons of the MT-ND4 gene (5'-ATG CTA AAA-3' coding for amino acids Met-Leu-Lys).[5] With respect to the MT-ND4L reading frame (+1), the MT-ND4 gene starts in the +3 reading frame: [CAA][TGC][TAA]AA versus CA[ATG][CTA][AAA].
The MT-ND4L gene produces an 11 kDa protein composed of 98 amino acids.[6][7] MT-ND4L 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-ND4L 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
MT-ND4L 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
Mitochondrial dysfunction resulting from variants of MT-ND4L, MT-ND1 and MT-ND2 have been linked to BMI in adults and implicated in metabolic disorders including obesity, diabetes and hypertension.[3]
A T>C mutation at position 10,663 in the mitochondrial gene MT-ND4L is known to cause Leber's Hereditary Optic Neuropathy (LHON). This mutation results in the replacement of the amino acid valine with alanine at position 65 of the protein ND4L, disrupting function of Complex I in the electron transport chain. It is unknown how this mutation leads to the loss of vision in LHON patients, but it may interrupt ATP production due to the impaired activity of Complex I. Mutations in other genes encoding subunits of Complex I, including MT-ND1, MT-ND2, MT-ND4, MT-ND5, and MT-ND6 are also known to cause LHON.[4]
References
- 1 2 "Entrez Gene: MT-ND4L NADH dehydrogenase subunit 4L".
- 1 2 3 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.
- 1 2 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. doi:10.1371/journal.pone.0105116. PMC 4143221. PMID 25153900.
- 1 2 "Leber Hereditary Optic Neuropathy". 1993. PMID 20301353.
- 1 2 Homo sapiens mitochondrion, complete genome. "Revised Cambridge Reference Sequence (rCRS): accession NC_012920", National Center for Biotechnology Information. Retrieved on 30 January 2016.
- ↑ 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.
- ↑ "NADH-ubiquinone oxidoreductase chain 4L". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
- ↑ "MT-ND4L - NADH-ubiquinone oxidoreductase chain 4L - Homo sapiens (Human)". UniProt.org: a hub for protein information. The UniProt Consortium.
Further reading
- Torroni A, Achilli A, Macaulay V, Richards M, Bandelt HJ (Jun 2006). "Harvesting the fruit of the human mtDNA tree". Trends in Genetics 22 (6): 339–45. doi:10.1016/j.tig.2006.04.001. PMID 16678300.
- 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. PMID 1301157.
- Lu X, Walker T, MacManus JP, Seligy VL (Jul 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. PMID 1377597.
- Marzuki S, Noer AS, Lertrit P, Thyagarajan D, Kapsa R, Utthanaphol P, Byrne E (Dec 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. PMID 1757091.
- Moraes CT, Andreetta F, Bonilla E, Shanske S, DiMauro S, Schon EA (Mar 1991). "Replication-competent human mitochondrial DNA lacking the heavy-strand promoter region". Molecular and Cellular Biology 11 (3): 1631–7. PMC 369459. PMID 1996112.
- 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 51 (1): 103–14. doi:10.1101/sqb.1986.051.01.013. PMID 3472707.
- Chomyn A, Cleeter MW, Ragan CI, Riley M, Doolittle RF, Attardi G (Oct 1986). "URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit". Science 234 (4776): 614–8. doi:10.1126/science.3764430. PMID 3764430.
- 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. doi:10.1038/314592a0. PMID 3921850.
- 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 (Apr 1981). "Sequence and organization of the human mitochondrial genome". Nature 290 (5806): 457–65. doi:10.1038/290457a0. PMID 7219534.
- Montoya J, Ojala D, Attardi G (Apr 1981). "Distinctive features of the 5'-terminal sequences of the human mitochondrial mRNAs". Nature 290 (5806): 465–70. doi:10.1038/290465a0. PMID 7219535.
- Horai S, Hayasaka K, Kondo R, Tsugane K, Takahata N (Jan 1995). "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. doi:10.1073/pnas.92.2.532. PMC 42775. PMID 7530363.
- Brown MD, Torroni A, Reckord CL, Wallace DC (1996). "Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations". Human Mutation 6 (4): 311–25. doi:10.1002/humu.1380060405. PMID 8680405.
- Arnason U, Xu X, Gullberg A (Feb 1996). "Comparison between the complete mitochondrial DNA sequences of Homo and the common chimpanzee based on nonchimeric sequences". Journal of Molecular Evolution 42 (2): 145–52. doi:10.1007/BF02198840. PMID 8919866.
- Polyak K, Li Y, Zhu H, Lengauer C, Willson JK, Markowitz SD, Trush MA, Kinzler KW, Vogelstein B (Nov 1998). "Somatic mutations of the mitochondrial genome in human colorectal tumours". Nature Genetics 20 (3): 291–3. doi:10.1038/3108. PMID 9806551.
- Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N (Oct 1999). "Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA". Nature Genetics 23 (2): 147. doi:10.1038/13779. PMID 10508508.
- Ingman M, Kaessmann H, Pääbo S, Gyllensten U (Dec 2000). "Mitochondrial genome variation and the origin of modern humans". Nature 408 (6813): 708–13. doi:10.1038/35047064. PMID 11130070.
- Finnilä S, Lehtonen MS, Majamaa K (Jun 2001). "Phylogenetic network for European mtDNA". American Journal of Human Genetics 68 (6): 1475–84. doi:10.1086/320591. PMC 1226134. PMID 11349229.
- Maca-Meyer N, González AM, Larruga JM, Flores C, Cabrera VM (2003). "Major genomic mitochondrial lineages delineate early human expansions". BMC Genetics 2: 13. doi:10.1186/1471-2156-2-13. PMC 55343. PMID 11553319.
- Herrnstadt C, Elson JL, Fahy E, Preston G, Turnbull DM, Anderson C, Ghosh SS, Olefsky JM, Beal MF, Davis RE, Howell N (May 2002). "Reduced-median-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups". American Journal of Human Genetics 70 (5): 1152–71. doi:10.1086/339933. PMC 447592. PMID 11938495.
- Silva WA, Bonatto SL, Holanda AJ, Ribeiro-Dos-Santos AK, Paixão BM, Goldman GH, Abe-Sandes K, Rodriguez-Delfin L, Barbosa M, Paçó-Larson ML, Petzl-Erler ML, Valente V, Santos SE, Zago MA (Jul 2002). "Mitochondrial genome diversity of Native Americans supports a single early entry of founder populations into America". American Journal of Human Genetics 71 (1): 187–92. doi:10.1086/341358. PMC 384978. PMID 12022039.
External links
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