NDUFA10

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10 is an is_associated_with::enzyme that in humans is encoded by the NDUFA10 is_associated_with::gene. The NDUFA10 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 subunits of 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. Furthermore, reduced NDUFA10 expression levels due to is_associated_with::FOXM1-directed hypermethylation are associated with human squamous cell carcinoma and may be related to other forms of cancer.

Structure
The NDUFA10 gene is located on the q arm of is_associated_with::chromosome 2 in position 37.3 and spans 68,031 base pairs. The gene produces a 41 kDa protein composed of 355 is_associated_with::amino acids. NDUFA10 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. NDUFA10 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 NDUFA10 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
NDUFA10 demonstrated significantly downregulated mRNA expression levels in human squamous cell carcinoma, due to is_associated_with::FOXM1-induced hypermethylation. is_associated_with::FOXM1 is a known oncogene that has been implicated in all human cancer types. It operates by inhibiting tumor suppressor genes through promoter hypermethylation, among other mechanisms.