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AliasesND4L, MTMT-NADH dehydrogenase, subunit 4L (complex I)
External IDsOMIM: 516004 MGI: 102497 HomoloGene: 5021 GeneCards: ND4L
Gene location (Human)
Mitochondrial DNA (human)
Chr.Mitochondrial DNA (human)[1]
Bandn/aStart10,470 bp[1]
End10,766 bp[1]
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr M: 0.01 – 0.01 MbChr M: 0.01 – 0.01 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse
Location of the MT-ND4L gene in the human mitochondrial genome. MT-ND4L is one of the seven NADH dehydrogenase mitochondrial genes (yellow boxes).

NADH-ubiquinone oxidoreductase chain 4L is a protein that in humans is encoded by the mitochondrial gene MT-ND4L.[5] 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.[6] Variants of MT-ND4L are associated with increased BMI in adults and Leber's Hereditary Optic Neuropathy (LHON).[7][8]


The MT-ND4L gene is located in human mitochondrial DNA from base pair 10,469 to 10,765.[5][9] 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).[9] 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.[10][11] 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.[6]


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).[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[edit]

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.[7]

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.[8]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000212907 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000065947 - 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. ^ a b "Entrez Gene: MT-ND4L NADH dehydrogenase subunit 4L".
  6. ^ 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.
  7. ^ a b 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. doi:10.1371/journal.pone.0105116. PMC 4143221. PMID 25153900.
  8. ^ a b Yu-Wai-Man P, Chinnery PF (1993). "Leber Hereditary Optic Neuropathy". PMID 20301353. Cite journal requires |journal= (help)
  9. ^ a b Homo sapiens mitochondrion, complete genome. "Revised Cambridge Reference Sequence (rCRS): accession NC_012920", National Center for Biotechnology Information. Retrieved on 30 January 2016.
  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 (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.
  11. ^ "NADH-ubiquinone oxidoreductase chain 4L". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  12. ^ "MT-ND4L - NADH-ubiquinone oxidoreductase chain 4L - Homo sapiens (Human)". a hub for protein information. The UniProt Consortium.

Further reading[edit]

External links[edit]