MT-ND1

NADH-ubiquinone oxidoreductase chain 1 is a is_associated_with::protein that in humans is encoded by the mitochondrial is_associated_with::gene MT-ND1. The ND1 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 the MT-ND1 gene are associated with is_associated_with::mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), is_associated_with::Leigh's syndrome (LS), is_associated_with::Leber's hereditary optic neuropathy (LHON) and increases in adult BMI.

Structure
MT-ND1 is located in mitochondrial DNA from base pair 3,307 to 4,262. The MT-ND1 gene produces a 36 kDa protein composed of 318 amino acids. MT-ND1 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-ND1 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-ND1 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-ND1 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-ND2, is_associated_with::MT-ND3, 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-ND1. The m.4171C>A/MT-ND1 mutation also leads to a Leigh-type phenotype as well as bilateral brainstem lesions affecting the vestibular nuclei, resulting in vision loss, vomiting and vertigo. 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.

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