MT-ND4

NADH-ubiquinone oxidoreductase chain 4 is a is_associated_with::protein that in humans is encoded by the mitochondrial is_associated_with::gene MT-ND4. The ND4 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-ND4 gene are associated with is_associated_with::age-related macular degeneration (AMD), is_associated_with::Leber's hereditary optic neuropathy (LHON), is_associated_with::mesial temporal lobe epilepsy (MTLE) and is_associated_with::cystic fibrosis.

Structure
MT-ND4 is located in mitochondrial DNA from base pair 10,760 to 12,137. The MT-ND4 gene produces a 52 kDa protein composed of 459 amino acids. MT-ND4 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-ND4 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-ND4 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.

Studies in is_associated_with::cystic fibrosis cases suggest that MT-ND4 expression is indirectly upregulated by the is_associated_with::cystic fibrosis transmembrane conductance regulator (CFTR) channel chloride transport activity. Channel flow double-electrode (CFDE) cells ectopically expressing wild-type CFTR channels were used to test the effect of CFTR chloride transport inhibitors is_associated_with::glibenclamide and CFTR(inh)172 and demonstrated a reduction in MT-ND4 expression.

Clinical significance
MT-ND4 is one of five SNPs associated with is_associated_with::age-related macular degeneration (AMD) in Mexican Americans.

is_associated_with::Leber's hereditary optic neuropathy (LHON) correlates with a mutation in the MT-ND4 gene in multiple families. The mutation at codon 340 results in the elimination of an Sfa NI site by the conversion of a highly conserved is_associated_with::arginine to a is_associated_with::histidine. This provides a simple diagnostic test by which to identify LHON, a maternally inherited disease that results in optic nerve degeneration and cardiac dysrythmia.

Amino acid changes in MT-ND4, is_associated_with::MT-ND5 and is_associated_with::MT-ATP8 resulting from mutations at the 11994, 8502 and 13,231 bp of mtDNA are significantly correlated in is_associated_with::mesial temporal lobe epilepsy (MTLE) patients with is_associated_with::hippocampal sclerosis. The 11994 C>T mutation to the MT-ND4 gene results in a Thr to Ile shift at the 412 position. Genome analysis has never been used in MTLE cases and could provide another diagnostic method in the disease.

MT-ND4 is downregulated in is_associated_with::cystic fibrosis, a disease that results from mutations in the is_associated_with::cystic fibrosis transmembrane conductance regulator (CFTR) channel.