NDUFA9

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9 is an is_associated_with::enzyme that in humans is encoded by the NDUFA9 is_associated_with::gene. The NDUFA9 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 NADH dehydrogenase (ubiquinone), also known as is_associated_with::Complex I, frequently lead to complex neurodegenerative diseases such as is_associated_with::Leigh's syndrome. In the case of NDUFA9, a mutation to the is_associated_with::MT-ND3 gene might interrupt their interaction and formation of subcomplexes, compromising is_associated_with::Complex I function and leading to disease.

Structure
The NDUFA9 gene is located on the p arm of is_associated_with::chromosome 12 in position 13.3 and spans 38,457 base pairs. The gene produces a 42.5 kDa protein composed of 377 is_associated_with::amino acids. NDUFA9 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. 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. NDUFA9 is one of about 31 hydrophobic subunits that form the transmembrane region of Complex I, but it is an accessory subunit that is believed not to be involved in catalysis. The predicted is_associated_with::secondary structure is primarily alpha helix, but the carboxy-terminal half of the protein has high potential to adopt a coiled-coil form. The amino-terminal part contains a putative beta sheet rich in hydrophobic amino acids that may serve as mitochondrial import signal.

Function
The human NDUFA9 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to is_associated_with::ubiquinone. 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
Decreased expression of NDUFA9 is associated with is_associated_with::Leigh's syndrome, a severe neurological disorder that typically arises in the first year of life, is characterized by progressive loss of mental and movement abilities, and typically results in death within a couple of years, usually due to respiratory failure. A mutation in the is_associated_with::MT-ND3 gene (tyrosine to cytosine at the 10191 position) results in a substitution of serine for proline, which may introduce instability of is_associated_with::Complex I due to the inability form subcomplexes between is_associated_with::MT-ND3 and NDUFA9. However, this genetic identification may not be suitable for prenatal testing because of the mutation's age and tissue dependence.