NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 is an
enzyme that in humans is encoded by the NDUFA12gene.[5][6][7] The NDUFA12 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.[8][9] Mutations in subunits of NADH dehydrogenase (ubiquinone), also known as
Complex I, frequently lead to complex neurodegenerative diseases such as
Leigh's syndrome that result from mitochondrial complex I deficiency.[7]
Structure
The NDUFA12 gene is located on the q arm of
chromosome 12 in position 22 and spans 32,386 base pairs.[7] The gene produces a 17 kDa protein composed of 145
amino acids.[10][11] NDUFA12 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.[8] 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. NDUFA12 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.[7][9][13]
Function
The human NDUFA12 gene codes for a subunit of
Complex I of the
respiratory chain, which transfers electrons from
NADH to
ubiquinone.[7]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.[8]
Clinical significance
Mutations to NDUFA12 are not frequently found to cause complex I deficiency on their own. NDUFA12 is an accessory subunit and the complex can still be found assembled and enzymatically active in its absence, though in reduced amounts and activity. However, a cytosine to tyrosine mutation at position 178 that leads to a premature stop codon has been found in place of
arginine at amino acid 60, leading to delayed early development, loss of motor abilities, and basal ganglia lesions typical of
Leigh's syndrome.[14]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Triepels R, Smeitink J, Loeffen J, Smeets R, Trijbels F, van den Heuvel L (Apr 2000). "Characterization of the human complex I NDUFB7 and 17.2-kDa cDNAs and mutational analysis of 19 genes of the HP fraction in complex I-deficient-patients". Human Genetics. 106 (4): 385–391.
doi:
10.1007/s004390000278.
PMID10830904.
S2CID1036688.
^
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.
PMID9763677.
S2CID46818955.
^Ton C, Hwang DM, Dempsey AA, Liew CC (Dec 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.
^Ostergaard E, Rodenburg RJ, van den Brand M, Thomsen LL, Duno M, Batbayli M, Wibrand F, Nijtmans L (Nov 2011). "Respiratory chain complex I deficiency due to NDUFA12 mutations as a new cause of Leigh syndrome". Journal of Medical Genetics. 48 (11): 737–40.
doi:
10.1136/jmg.2011.088856.
PMID21617257.
S2CID33078321.
Further reading
Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174.
doi:
10.1016/0378-1119(94)90802-8.
PMID8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156.
doi:
10.1016/S0378-1119(97)00411-3.
PMID9373149.
NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 is an
enzyme that in humans is encoded by the NDUFA12gene.[5][6][7] The NDUFA12 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.[8][9] Mutations in subunits of NADH dehydrogenase (ubiquinone), also known as
Complex I, frequently lead to complex neurodegenerative diseases such as
Leigh's syndrome that result from mitochondrial complex I deficiency.[7]
Structure
The NDUFA12 gene is located on the q arm of
chromosome 12 in position 22 and spans 32,386 base pairs.[7] The gene produces a 17 kDa protein composed of 145
amino acids.[10][11] NDUFA12 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.[8] 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. NDUFA12 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.[7][9][13]
Function
The human NDUFA12 gene codes for a subunit of
Complex I of the
respiratory chain, which transfers electrons from
NADH to
ubiquinone.[7]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.[8]
Clinical significance
Mutations to NDUFA12 are not frequently found to cause complex I deficiency on their own. NDUFA12 is an accessory subunit and the complex can still be found assembled and enzymatically active in its absence, though in reduced amounts and activity. However, a cytosine to tyrosine mutation at position 178 that leads to a premature stop codon has been found in place of
arginine at amino acid 60, leading to delayed early development, loss of motor abilities, and basal ganglia lesions typical of
Leigh's syndrome.[14]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Triepels R, Smeitink J, Loeffen J, Smeets R, Trijbels F, van den Heuvel L (Apr 2000). "Characterization of the human complex I NDUFB7 and 17.2-kDa cDNAs and mutational analysis of 19 genes of the HP fraction in complex I-deficient-patients". Human Genetics. 106 (4): 385–391.
doi:
10.1007/s004390000278.
PMID10830904.
S2CID1036688.
^
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.
PMID9763677.
S2CID46818955.
^Ton C, Hwang DM, Dempsey AA, Liew CC (Dec 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.
^Ostergaard E, Rodenburg RJ, van den Brand M, Thomsen LL, Duno M, Batbayli M, Wibrand F, Nijtmans L (Nov 2011). "Respiratory chain complex I deficiency due to NDUFA12 mutations as a new cause of Leigh syndrome". Journal of Medical Genetics. 48 (11): 737–40.
doi:
10.1136/jmg.2011.088856.
PMID21617257.
S2CID33078321.
Further reading
Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174.
doi:
10.1016/0378-1119(94)90802-8.
PMID8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156.
doi:
10.1016/S0378-1119(97)00411-3.
PMID9373149.