Species Human Entrez 4697 | Human Mouse Ensembl ENSG00000189043 | |
Aliases NDUFA4, CI-9k, CI-MLRQ, MLRQ, mitochondrial complex associated External IDs MGI: 107686 HomoloGene: 37629 GeneCards: NDUFA4 | ||
NDUFA4, mitochondrial complex associated is a protein that in humans is encoded by the NDUFA4 gene. The NDUFA3 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in the NDUFA4 gene are associated with Leigh's syndrome.
Contents
Structure
The NDUFA4 gene is located on the p arm of chromosome 7 at position 21.3 with a total length of 8,234 base pairs. The NDUFA4 gene produces a 9.4 kDa protein composed of 81 amino acids.
NDUFA4 has traditionally been defined as a subunit of the enzyme NADH dehydrogenase (ubiquinone) (Complex I), the largest of the respiratory complexes. The structure of Complex I is L-shaped with a long, hydrophobic transmembrane domain and a 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 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 NADH:ubiquinone oxidoreductase complex at the inner mitochondrial membrane.
More recent research has demonstrated that no perturbation of Complex I occurs upon NDUFA4 deletion, calling into question its role in this complex. It has been demonstrated that NDUFA4 plays a role in Complex IV function and biogenesis, however, with some authors suggesting that the NDUFA4 gene be renamed and the structure of both Complex I and Complex IV be re-evaluated.
Function
The human NDUFA1 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. Mammalian complex I of mitochondrial respiratory chain is composed of 45 different subunits; the protein encoded by this gene belongs to the complex I 9kDa subunit family and it has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the 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 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
Mutations in the NDUFA4 gene can result in Leigh's syndrome, a severe neurological disorder that typically arises in the first year of life. Disruption of Complex IV, also called cytochrome c oxidase or COX, is the most common cause of Leigh syndrome. Given that NDUFA4 has only recently been identified as a subunit of Complex IV rather than Complex I, patients with previously unexplained COX deficiencies could be genetically tested for NDUFA4 mutations.
Interactions
NDUFA4 has many protein-protein interactions, including ubiquitin proteins such as ubiquitin C and UBL4A, as well as CUL3 and PARK7.