NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10 is an
enzyme that in humans is encoded by the NDUFA10gene.[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,
hydrophobictransmembrane 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]
^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.
PMID9878551.
^
abcVoet D,
Voet JG, Pratt CW (2013). "Chapter 18". Fundamentals of biochemistry: life at the molecular level (4th ed.). Hoboken, NJ: Wiley. pp. 581–620.
ISBN978-0-470-54784-7.
^
abEmahazion 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 (inactive 2024-06-08).
PMID9763677.
S2CID46818955.{{
cite journal}}: CS1 maint: DOI inactive as of June 2024 (
link)
^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.
PMID9425316.
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.
PMID16806233.
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.
PMID12665801.
S2CID23783563.
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.
PMID8088812.
NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10 is an
enzyme that in humans is encoded by the NDUFA10gene.[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,
hydrophobictransmembrane 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]
^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.
PMID9878551.
^
abcVoet D,
Voet JG, Pratt CW (2013). "Chapter 18". Fundamentals of biochemistry: life at the molecular level (4th ed.). Hoboken, NJ: Wiley. pp. 581–620.
ISBN978-0-470-54784-7.
^
abEmahazion 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 (inactive 2024-06-08).
PMID9763677.
S2CID46818955.{{
cite journal}}: CS1 maint: DOI inactive as of June 2024 (
link)
^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.
PMID9425316.
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.
PMID16806233.
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.
PMID12665801.
S2CID23783563.
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.
PMID8088812.