MT-ND4L

NADH-ubiquinone oxidoreductase chain 4L is a is_associated_with::protein that in humans is encoded by the mitochondrial is_associated_with::gene MT-ND4L. The ND4L protein is a subunit of is_associated_with::NADH dehydrogenase (ubiquinone), which is located in the is_associated_with::mitochondrial inner membrane and is the largest of the five complexes of the is_associated_with::electron transport chain. Variants of MT-ND4L are associated with increased BMI in adults and is_associated_with::Leber's Hereditary Optic Neuropathy (LHON).

Structure
MT-ND4L is located in mitochondrial DNA from base pair 10,469 to 10,765. The gene produces an 11 kDa protein composed of 98 amino acids. MT-ND4L is one of seven mitochondrially-encoded subunits of the enzyme is_associated_with::NADH dehydrogenase (ubiquinone). Also known as is_associated_with::Complex I, it is the largest of the respiratory complexes. The structure is L-shaped with a long, is_associated_with::hydrophobic is_associated_with::transmembrane domain and a is_associated_with::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.

Function
MT-ND4L is a subunit of the respiratory chain is_associated_with::Complex I that is believed to belong to the minimal assembly of core proteins required to catalyze is_associated_with::NADH dehydrogenation and is_associated_with::electron transfer to is_associated_with::ubiquinone (coenzyme Q10). Initially, is_associated_with::NADH binds to Complex I and transfers two electrons to the is_associated_with::isoalloxazine ring of the is_associated_with::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 is_associated_with::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.

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

A T>C mutation at position 10,663 in the mitochondrial gene MT-ND4L is known to cause is_associated_with::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 is_associated_with::Complex I in the is_associated_with::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 is_associated_with::Complex I. Mutations in other genes encoding subunits of is_associated_with::Complex I, including is_associated_with::MT-ND1, is_associated_with::MT-ND2, is_associated_with::MT-ND4, is_associated_with::MT-ND5, and is_associated_with::MT-ND6 are also known to cause LHON.