NADH dehydrogenase (ubiquinone), alpha 1

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 is a is_associated_with::protein that in humans is encoded by the NDUFA1 is_associated_with::gene. The NDUFA1 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. Mutations in the NDUFA1 gene are associated with mitochondrial is_associated_with::Complex I deficiency.

Structure
The NDUFA1 gene is located on the long q arm of the is_associated_with::X chromosome at position 24 and it spans 5,176 base pairs. The NDUFA1 gene produces an 8.1 kDa protein composed of 70 is_associated_with::amino acids. NDUFA1 is a subunit of the enzyme is_associated_with::NADH dehydrogenase (ubiquinone), 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 centers and the NADH binding site. NDUFA1 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an is_associated_with::alpha helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of Complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and that the hydrophobic domain acts as an anchor for the is_associated_with::NADH dehydrogenase (ubiquinone) complex at the inner mitochondrial membrane.

Function
The human NDUFA1 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to is_associated_with::ubiquinone. However, NDUFA1 is an accessory subunit of the complex that is believed not to be involved in catalysis. 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
Mitochondrial complex I deficiency (MT-C1D) is caused by mutations affecting the NDUFA1 gene. Complex I deficiency is a disorder of the mitochondrial respiratory chain that causes a wide range of clinical manifestations, from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, is_associated_with::Leigh syndrome, is_associated_with::Leber's hereditary optic neuropathy, and some forms of is_associated_with::Parkinson's disease.