MT-ND3

Mitochondrially encoded NADH dehydrogenase 3 is a is_associated_with::protein that in humans is encoded by the mitochondrial is_associated_with::gene MT-ND3. The ND3 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-ND3 are associated with is_associated_with::Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), is_associated_with::Leigh's syndrome (LS) and is_associated_with::Leber's hereditary optic neuropathy (LHON).

Structure
MT-ND3 is located in mitochondrial DNA from base pair 10,059 to 10,404. The MT-ND3 gene produces a 13 kDa protein composed of 115 amino acids. MT-ND3 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-ND3 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-ND3 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
Pathogenic variants of the mitochondrial gene MT-ND3 are known to cause mtDNA-associated is_associated_with::Leigh syndrome, as are variants of is_associated_with::MT-ATP6, is_associated_with::MT-TL1, is_associated_with::MT-TK, is_associated_with::MT-TW, MT-TV, is_associated_with::MT-ND1, is_associated_with::MT-ND2, is_associated_with::MT-ND4, is_associated_with::MT-ND5, is_associated_with::MT-ND6 and is_associated_with::MT-CO3. Abnormalities in mitochondrial energy generation result in neurodegenerative disorders like Leigh syndrome, which is characterized by an onset of symptoms between 12 months and three years of age. The symptoms frequently present themselves following a viral infection and include movement disorders and peripheral neuropathy, as well as hypotonia, spasticity and cerebellar ataxia. Roughly half of affected patients die of respiratory or cardiac failure by the age of three. is_associated_with::Leigh syndrome is a maternally inherited disorder and its diagnosis is established through genetic testing of the aforementioned mitochondrial genes, including MT-ND3. These is_associated_with::complex I genes have been associated with a variety of neurodegenerative disorders, including is_associated_with::Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (is_associated_with::MELAS) and the previously mentioned is_associated_with::Leigh syndrome.