NDUFA10

NDUFA10
Identifiers
Aliases	NDUFA10 , CI-42KD, CI-42k, NADH:ubiquinone oxidoreductase subunit A10, MC1DN22
External IDs	OMIM: 603835 MGI: 1914523 HomoloGene: 15342 GeneCards: NDUFA10
Gene location (Human) Chr. Chromosome 2 (human) [1] Band 2q37.3 Start 239,892,450 bp [1] End 240,025,743 bp [1]
Gene location (Mouse) Chr. Chromosome 1 (mouse) [2] Band 1|1 D Start 92,366,732 bp [2] End 92,401,582 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in left ventricle right ventricle Right adrenal gland Left adrenal gland rectum gastrocnemius muscle skin of abdomen body of stomach thoracic diaphragm triceps brachii muscle Top expressed in right ventricle digastric muscle sternocleidomastoid muscle triceps brachii muscle temporal muscle vastus lateralis muscle facial motor nucleus anterior horn of spinal cord ankle crypt of lieberkuhn of small intestine More reference expression data BioGPS More reference expression data
Gene ontology Molecular function NADH dehydrogenase (ubiquinone) activity Cellular component mitochondrial inner membrane myelin sheath mitochondrial matrix respirasome mitochondrion mitochondrial respiratory chain complex I cytoplasm Biological process mitochondrial electron transport, NADH to ubiquinone mitochondrial respiratory chain complex I assembly Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4705 67273 Ensembl ENSG00000130414 ENSMUSG00000026260 UniProt O95299 Q99LC3 RefSeq (mRNA) NM_004544 NM_001322019 NM_001322020 NM_024197 RefSeq (protein) NP_001308948 NP_001308949 NP_004535 NP_077159 Location (UCSC) Chr 2: 239.89 – 240.03 Mb Chr 1: 92.37 – 92.4 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10 is an enzyme that in humans is encoded by the NDUFA10 gene. ^{[5] [6]} The NDUFA10 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. ^{[7] [8]} Mutations in subunits of NADH dehydrogenase (ubiquinone), also known as Complex I, frequently lead to complex neurodegenerative diseases such as Leigh's syndrome. ^[5] Furthermore, reduced NDUFA10 expression levels due to FOXM1-directed hypermethylation are associated with human squamous cell carcinoma and may be related to other forms of cancer. ^[9]

Structure

The NDUFA10 gene is located on the q arm of chromosome 2 in position 37.3 and spans 68,031 base pairs. ^[5] The gene produces a 41 kDa protein composed of 355 amino acids. ^{[10] [11]} NDUFA10 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. ^[7] 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. 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. ^[12] The predicted 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. ^{[5] [8] [13]}

Function

The human NDUFA10 gene codes for a subunit of Complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. ^[5] 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. ^[7]

Clinical significance

NDUFA10 demonstrated significantly downregulated mRNA expression levels in human squamous cell carcinoma, due to FOXM1-induced hypermethylation. 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. ^[9] Mutations in NDUFA10 have also been associated with Leigh disease resulting from complex I deficiency. ^[14]

Interactions

NDUFA10 has been shown to have 56 binary protein-protein interactions including 55 co-complex interactions. NDUFA10 appears to interact with RAB8A. ^[15]

References

1. GRCh38: Ensembl release 89: ENSG00000130414 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000026260 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: NDUFA10 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 10".
6. Loeffen JL, Triepels RH, van den Heuvel LP, Schuelke M, Buskens CA, Smeets RJ, Trijbels JM, Smeitink JA (December 1998). "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. doi:10.1006/bbrc.1998.9786. PMID   9878551.
7. Voet D, Voet JG, Pratt CW (2013). "Chapter 18". Fundamentals of biochemistry: life at the molecular level (4th ed.). Hoboken, NJ: Wiley. pp. 581–620. ISBN   978-0-470-54784-7.
8. Emahazion T, Beskow A, Gyllensten U, Brookes AJ (Nov 1998). "Intron based radiation hybrid mapping of 15 complex I genes of the human electron transport chain". Cytogenetics and Cell Genetics. 82 (1–2): 115–9. doi:10.1159/000015082. PMID   9763677. S2CID   46818955.
9. Teh MT, Gemenetzidis E, Patel D, Tariq R, Nadir A, Bahta AW, Waseem A, Hutchison IL (2012). "FOXM1 induces a global methylation signature that mimics the cancer epigenome in head and neck squamous cell carcinoma". PLOS ONE. 7 (3): e34329. Bibcode:2012PLoSO...734329T. doi: 10.1371/journal.pone.0034329 . PMC   3312909 . PMID   22461910.
10. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC   4076475 . PMID   23965338.
11. "NDUFA10 - NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
12. "NDUFA10 - NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10". UniProt.org. The UniProt Consortium.
13. Ton C, Hwang DM, Dempsey AA, Liew CC (December 1997). "Identification and primary structure of five human NADH-ubiquinone oxidoreductase subunits". Biochemical and Biophysical Research Communications. 241 (2): 589–94. doi:10.1006/bbrc.1997.7707. PMID   9425316.
14. Hoefs SJ, van Spronsen FJ, Lenssen EW, Nijtmans LG, Rodenburg RJ, Smeitink JA, van den Heuvel LP (March 2011). "NDUFA10 mutations cause complex I deficiency in a patient with Leigh disease". European Journal of Human Genetics. 19 (3): 270–4. doi:10.1038/ejhg.2010.204. PMC   3061993 . PMID   21150889.
15. "56 binary interactions found for search term NDUFA10". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-08-25.

Further reading

• Smeitink J, van den Heuvel L (June 1999). "Human mitochondrial complex I in health and disease". American Journal of Human Genetics. 64 (6): 1505–10. doi:10.1086/302432. PMC   1377894 . PMID   10330338.
• Ma J, Dempsey AA, Stamatiou D, Marshall KW, Liew CC (March 2007). "Identifying leukocyte gene expression patterns associated with plasma lipid levels in human subjects". Atherosclerosis. 191 (1): 63–72. doi:10.1016/j.atherosclerosis.2006.05.032. PMID   16806233.
• Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J (May 2003). "Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides". Nature Biotechnology. 21 (5): 566–9. doi:10.1038/nbt810. PMID   12665801. S2CID   23783563.
• Baens M, Chaffanet M, Aerssens J, Cassiman JJ, Marynen P (May 1994). "Assignment of the gene for the human proliferating cell nucleolar protein P120 (NOL1) to chromosome 12p13 by fluorescence in situ hybridization and polymerase chain reaction with somatic cell hybrids". Genomics. 21 (1): 296–7. doi:10.1006/geno.1994.1267. PMID   8088812.

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