NDUFS8 is located on the q arm of chromosome 11 in position 13.2.[3] The NDUFS8 gene produces a 23.7 kDa protein composed of 210 amino acids.[6][7] The encoded protein, TYKY, contains two 4Fe4S ferredoxin consensus patterns which are believed to be iron-sulfur cluster N-2 binding sites.[8] Studies of other subunits of Complex I have suggested that the subunits TYKY, PSST, 49 kDa, ND1, and ND5 interact with iron-sulfur clusters to form the catalytic core of NADH dehydrogenase (ubiquinone).[9]
Function
This gene encodes a subunit of mitochondrial NADH:ubiquinone oxidoreductase, or Complex I, a multimeric enzyme of the respiratory chain responsible for NADH oxidation, ubiquinone reduction, and the ejection of protons from mitochondria. The encoded protein is involved in the binding of two of the six to eight iron-sulfur clusters of Complex I and, as such, is required in the electron transfer process.[3]
NDUFS8 mutations have also been associated with Leigh syndrome. Leigh syndrome is an early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, dysphagia and lactic acidosis.[4] One case report of a pathogenic mutation in NDUFS8 found that it resulted in complex I mitochondrial deficiency and a diagnosis of Leigh syndrome. The patient’s symptoms included apnea, cyanosis, hypercarbia, hypotonia, brisk tendon reflexes, ankle clonus, and erratic seizures. Further analysis revealed increased lactate, cerebral lesions, and a hypertrophic obstructive cardiomyopathy.[8]
Interactions
In addition to co-subunits for complex I, NDUFS8 has protein-protein interactions with MLH1 and GEM.[10][11]
References
↑de Sury R, Martinez P, Procaccio V, Lunardi J, Issartel JP (July 1998). "Genomic structure of the human NDUFS8 gene coding for the iron-sulfur TYKY subunit of the mitochondrial NADH:ubiquinone oxidoreductase". Gene. 215 (1): 1–10. doi:10.1016/S0378-1119(98)00275-3. PMID9666055.
↑Procaccio V, Depetris D, Soularue P, Mattei MG, Lunardi J, Issartel JP (March 1997). "cDNA sequence and chromosomal localization of the NDUFS8 human gene coding for the 23 kDa subunit of the mitochondrial complex I". Biochimica et Biophysica Acta. 1351 (1–2): 37–41. doi:10.1016/s0167-4781(97)00020-1. PMID9116042.
↑Donald Voet; Judith G. Voet; Charlotte W. Pratt (2013). "18". Fundamentals of biochemistry : life at the molecular level (4th ed.). Hoboken, NJ: Wiley. pp. 581–620. ISBN9780470547847.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Dunbar DR, Shibasaki Y, Dobbie L, Andersson B, Brookes AJ (1997). "In situ hybridisation mapping of genomic clones for five human respiratory chain complex I genes". Cytogenetics and Cell Genetics. 78 (1): 21–4. doi:10.1159/000134618. PMID9345899.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Triepels RH, Hanson BJ, van den Heuvel LP, Sundell L, Marusich MF, Smeitink JA, Capaldi RA (March 2001). "Human complex I defects can be resolved by monoclonal antibody analysis into distinct subunit assembly patterns". The Journal of Biological Chemistry. 276 (12): 8892–7. doi:10.1074/jbc.M009903200. PMID11112787.
Lescuyer P, Martinez P, Lunardi J (March 2002). "YY1 and Sp1 activate transcription of the human NDUFS8 gene encoding the mitochondrial complex I TYKY subunit". Biochimica et Biophysica Acta. 1574 (2): 164–74. doi:10.1016/s0167-4781(01)00377-3. PMID11955626.
Murray J, Taylor SW, Zhang B, Ghosh SS, Capaldi RA (September 2003). "Oxidative damage to mitochondrial complex I due to peroxynitrite: identification of reactive tyrosines by mass spectrometry". The Journal of Biological Chemistry. 278 (39): 37223–30. doi:10.1074/jbc.M305694200. PMID12857734.
Ugalde C, Janssen RJ, van den Heuvel LP, Smeitink JA, Nijtmans LG (March 2004). "Differences in assembly or stability of complex I and other mitochondrial OXPHOS complexes in inherited complex I deficiency". Human Molecular Genetics. 13 (6): 659–67. doi:10.1093/hmg/ddh071. PMID14749350.