TheMT-ND4L gene is located in human mitochondrial DNA from base pair 10,469 to 10,765.[5][9] TheMT-ND4L gene produces an 11 kDa protein composed of 98 amino acids.[10][11] MT-ND4L is one of seven mitochondrial genes encoding subunits of the enzymeNADH dehydrogenase (ubiquinone), together withMT-ND1,MT-ND2,MT-ND3,MT-ND4,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. 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]
An unusual feature of the humanMT-ND4L gene is the 7-nucleotidegene overlap of its last three codons (5'-CAA TGC TAA-3' coding for Gln, Cys and Stop) with the first three codons of theMT-ND4 gene (5'-ATG CTA AAA-3' coding for amino acids Met-Leu-Lys).[9] With respect to theMT-ND4Lreading frame (+1), theMT-ND4 gene starts in the +3 reading frame:[CAA][TGC][TAA]AA versusCA[ATG][CTA][AAA].
The MT-ND4L product is a subunit of the respiratory chainComplex I that is believed 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]
Mitochondrial dysfunction resulting from variants of MT-ND4L,MT-ND1 andMT-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 causeLeber'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 ofComplex I in theelectron 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 ofComplex I. Mutations in other genes encoding subunits ofComplex I, includingMT-ND1,MT-ND2,MT-ND4,MT-ND5, andMT-ND6 are also known to cause LHON.[8]
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