NADH dehydrogenase (ubiquinone), alpha 1

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Species	Human	Mouse
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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.

Further reading

• Smeitink J, van den Heuvel L (1999). "Human mitochondrial complex I in health and disease". Am. J. Hum. Genet. 64 (6): 1505–10. doi:10.1086/302432. PMC 1377894. PMID 10330338.
• Tretter L, Sipos I, Adam-Vizi V (2004). "Initiation of neuronal damage by complex I deficiency and oxidative stress in Parkinson's disease". Neurochem. Res. 29 (3): 569–77. doi:10.1023/B:NERE.0000014827.94562.4b. PMID 15038604.
• Frattini A, Faranda S, Bagnasco L, et al. (1997). "Identification of a new member (ZNF183) of the Ring finger gene family in Xq24-25". Gene. 192 (2): 291–8. doi:10.1016/S0378-1119(97)00108-X. PMID 9224902.
• Loeffen JL, Triepels RH, van den Heuvel LP, et al. (1999). "cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase: human complex I cDNA characterization completed". Biochem. Biophys. Res. Commun. 253 (2): 415–22. doi:10.1006/bbrc.1998.9786. PMID 9878551.
• Au HC, Seo BB, Matsuno-Yagi A, et al. (1999). "The NDUFA1 gene product (MWFE protein) is essential for activity of complex I in mammalian mitochondria". Proc. Natl. Acad. Sci. U.S.A. 96 (8): 4354–9. doi:10.1073/pnas.96.8.4354. PMC 16336. PMID 10200266.
• Yadava N, Potluri P, Smith EN, et al. (2002). "Species-specific and mutant MWFE proteins. Their effect on the assembly of a functional mammalian mitochondrial complex I.". J. Biol. Chem. 277 (24): 21221–30. doi:10.1074/jbc.M202016200. PMID 11937507.
• Man PY, Brown DT, Wehnert MS, et al. (2002). "NDUFA-1 is not a nuclear modifier gene in Leber hereditary optic neuropathy". Neurology. 58 (12): 1861–2. doi:10.1212/wnl.58.12.1861. PMID 12084895.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Mamelak AJ, Kowalski J, Murphy K, et al. (2005). "Downregulation of NDUFA1 and other oxidative phosphorylation-related genes is a consistent feature of basal cell carcinoma". Exp. Dermatol. 14 (5): 336–48. doi:10.1111/j.0906-6705.2005.00278.x. PMID 15854127.
• Vogel RO, Dieteren CE, van den Heuvel LP, et al. (2007). "Identification of mitochondrial complex I assembly intermediates by tracing tagged NDUFS3 demonstrates the entry point of mitochondrial subunits". J. Biol. Chem. 282 (10): 7582–90. doi:10.1074/jbc.M609410200. PMID 17209039.
• Fernandez-Moreira D, Ugalde C, Smeets R, et al. (2007). "X-linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy". Ann. Neurol. 61 (1): 73–83. 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.