The MT-ND6 gene is located in human mitochondrial DNA from base pair 14,149 to 14,673. MT-ND6 is the only protein-coding gene located on the L-strand of the human mitogenome. The encoded protein is 18 kDa and composed of 172 amino acids. MT-ND6 is one of seven mitochondrial genes encoding subunits of the enzyme NADH dehydrogenase, together with MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, and MT-ND5. Also known as Complex I, this enzyme is the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobictransmembrane domain and a 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
The MT-ND6 product 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. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotideprosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur clusters in the prosthetic arm and finally to coenzyme Q10, which is reduced to ubiquinol. 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 Leber's hereditary optic neuropathy. 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 Leber's hereditary optic neuropathy. These genetic changes appear to prevent Complex I from interacting normally with ubiquinone, which may affect the generation of ATP and may also increase the production within mitochondria of potentially harmful molecules called reactive oxygen species. 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. 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 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 dystonia, which involves involuntary muscle contractions, tremors, and other uncontrolled movements. This mutation appears to disrupt the normal assembly or activity of 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.
