Biology:NADH dehydrogenase (ubiquinone), alpha 1

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

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

Structure

The NDUFA1 gene is located on the long q arm of the X chromosome at position 24 and it spans 5,176 base pairs. The NDUFA1 gene produces an 8.1 kDa protein composed of 70 amino acids. NDUFA1 is a subunit of the enzyme NADH dehydrogenase (ubiquinone), the largest of the respiratory complexes. The structure 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. 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 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 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 ubiquinone. However, NDUFA1 is an accessory subunit of the complex that is believed not to be involved in catalysis. 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

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, Leigh syndrome, Leber's hereditary optic neuropathy, and some forms of Parkinson's disease. Mutations on the X chromosome that affect this gene have included the G94C mutation, which has been associated with lactic acidosis, hypotonia, increased beta-hydroxybutyrate/acetoacetate ratio, and complex I deficiency.

Interactions

NDUFA1 has been shown to have 7 binary protein-protein interactions including 3 co-complex interactions. NDUFA1 appears to interact with GOLGB1, TRIM63, and SMURF2.

Further reading

• "Human mitochondrial complex I in health and disease". American Journal of Human Genetics 64 (6): 1505–10. June 1999. doi:10.1086/302432. PMID 10330338. 
• "Initiation of neuronal damage by complex I deficiency and oxidative stress in Parkinson's disease". Neurochemical Research 29 (3): 569–77. March 2004. doi:10.1023/B:NERE.0000014827.94562.4b. PMID 15038604. 
• "Identification of a new member (ZNF183) of the Ring finger gene family in Xq24-25". Gene 192 (2): 291–8. June 1997. doi:10.1016/S0378-1119(97)00108-X. PMID 9224902. 
• "cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase: human complex I cDNA characterization completed". Biochemical and Biophysical Research Communications 253 (2): 415–22. December 1998. doi:10.1006/bbrc.1998.9786. PMID 9878551. 
• "The NDUFA1 gene product (MWFE protein) is essential for activity of complex I in mammalian mitochondria". Proceedings of the National Academy of Sciences of the United States of America 96 (8): 4354–9. April 1999. doi:10.1073/pnas.96.8.4354. PMID 10200266. Bibcode: 1999PNAS...96.4354A. 
• "Species-specific and mutant MWFE proteins. Their effect on the assembly of a functional mammalian mitochondrial complex I". The Journal of Biological Chemistry 277 (24): 21221–30. June 2002. doi:10.1074/jbc.M202016200. PMID 11937507. 
• "NDUFA-1 is not a nuclear modifier gene in Leber hereditary optic neuropathy". Neurology 58 (12): 1861–2. June 2002. doi:10.1212/wnl.58.12.1861. PMID 12084895. 
• "Downregulation of NDUFA1 and other oxidative phosphorylation-related genes is a consistent feature of basal cell carcinoma". Experimental Dermatology 14 (5): 336–48. May 2005. doi:10.1111/j.0906-6705.2005.00278.x. PMID 15854127. 
• "Identification of mitochondrial complex I assembly intermediates by tracing tagged NDUFS3 demonstrates the entry point of mitochondrial subunits". The Journal of Biological Chemistry 282 (10): 7582–90. March 2007. doi:10.1074/jbc.M609410200. PMID 17209039. 
• "X-linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy". Annals of Neurology 61 (1): 73–83. January 2007. doi:10.1002/ana.21036. PMID 17262856. 

This article incorporates text from the United States National Library of Medicine, which is in the public domain.