MT-ND6

NADH-ubiquinone oxidoreductase chain 6 is a is_associated_with::protein that in humans is encoded by the mitochondrial is_associated_with::gene MT-ND6 is_associated_with::gene. The ND6 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. Variations in the MT-ND6 gene are associated with is_associated_with::Leigh's syndrome, is_associated_with::Leber's hereditary optic neuropathy (LHON) and is_associated_with::dystonia.

Structure
The MT-ND6 gene is located in mitochondrial DNA from base pair 14,149 to 14,673. The encoded protein is 18 kDa and composed of 172 amino acids. MT-ND6 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-ND6 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-ND6 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
A T>C mutation at the 14484 base pair in the MT-ND6 gene has been identified in people with is_associated_with::Leber's hereditary optic neuropathy (LHON). This common MT-ND6 mutation is responsible for about 14 percent of all cases of LHON, and it is the most common cause of this disorder among people of French Canadian descent. This mutation changes a single amino acid in the NADH dehydrogenase 6 protein at position 64, from methionine to valine. The T14484C mutation is associated with a good long-term prognosis; affected people with this genetic change have a 37 percent to 65 percent chance of some visual recovery. Researchers are investigating how mutations in the MT-ND6 gene lead to is_associated_with::Leber's hereditary optic neuropathy. These genetic changes appear to prevent is_associated_with::Complex I from interacting normally with is_associated_with::ubiquinone, which may affect the generation of ATP and may also increase the production within mitochondria of potentially harmful molecules called is_associated_with::reactive oxygen species (ROS). It remains unclear, however, why the effects of these mutations are often limited to the nerve that relays visual information from the eye to the brain (the optic nerve). Additional genetic and environmental factors probably contribute to the vision loss and other medical problems associated with Leber hereditary optic neuropathy.

A G>A mutation at the 14459 base pair in the MT-ND6 gene also has been identified in a small number of people with is_associated_with::Leigh's syndrome, a progressive brain disorder that typically appears in infancy or early childhood. Affected children may experience vomiting, seizures, delayed development, muscle weakness, and problems with movement. Heart disease, kidney problems, and difficulty breathing can also occur in people with this disorder. This MT-ND6 G14459A mutation replaces the amino acid alanine with the amino acid valine at protein position 72 in the NADH-ubiquinone oxidoreductase chain 6 protein. This genetic change also has been found in people with LHON and a movement disorder called is_associated_with::dystonia, which involves involuntary muscle contractions, tremors, and other uncontrolled movements. This mutation appears to disrupt the normal assembly or activity of is_associated_with::complex I in mitochondria. It is not known, however, how this MT-ND6 gene alteration is related to the specific features of Leigh syndrome, LHON, or dystonia. It also remains unclear why a single mutation can cause such varied signs and symptoms in different people.

Interactions
MT-ND6 interacts with is_associated_with::NDUFS3 and is_associated_with::YME1L1.