Mitochondrialcomplex I is the first multimeric complex of the respiratory chain that catalyzes the NADH oxidation with concomitant ubiquinone reduction and proton ejection out of the mitochondria. Mammalian mitochondrial complex I is an assembly of at least 43 different subunits. Seven of the subunits are encoded by the mitochondrial genome; the remainder are the products of nuclear genes. The iron-sulfur protein (IP) fraction of complex I is made up of 7 subunits, including NDUFS2.
Mutations in the NDUFS2 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders. Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible. However, the majority of cases are caused by mutations in nuclear-encoded genes. It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.
^Procaccio V, de Sury R, Martinez P, Depetris D, Rabilloud T, Soularue P et al. (Jun 1998). "Mapping to 1q23 of the human gene (NDUFS2) encoding the 49-kDa subunit of the mitochondrial respiratory Complex I and immunodetection of the mature protein in mitochondria". Mammalian Genome9 (6): 482–4. doi:10.1007/s003359900803. PMID9585441.
^Kirby DM, Salemi R, Sugiana C, Ohtake A, Parry L, Bell KM et al. (Sep 2004). "NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency". The Journal of Clinical Investigation114 (6): 837–45. doi:10.1172/JCI20683. PMID15372108.
^McFarland R, Kirby DM, Fowler KJ, Ohtake A, Ryan MT, Amor DJ et al. (Jan 2004). "De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency". Annals of Neurology55 (1): 58–64. doi:10.1002/ana.10787. PMID14705112.
^Haack TB, Haberberger B, Frisch EM, Wieland T, Iuso A, Gorza M et al. (Apr 2012). "Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing". Journal of Medical Genetics49 (4): 277–83. doi:10.1136/jmedgenet-2012-100846. PMID22499348.
^Triepels RH, Van Den Heuvel LP, Trijbels JM, Smeitink JA (2001). "Respiratory chain complex I deficiency". American Journal of Medical Genetics106 (1): 37–45. doi:10.1002/ajmg.1397. PMID11579423.
^Robinson BH (May 1998). "Human complex I deficiency: clinical spectrum and involvement of oxygen free radicals in the pathogenicity of the defect". Biochimica Et Biophysica Acta1364 (2): 271–86. PMID9593934.
Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene138 (1-2): 171–4. 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". Gene200 (1-2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Loeffen J, van den Heuvel L, Smeets R, Triepels R, Sengers R, Trijbels F et al. (Jun 1998). "cDNA sequence and chromosomal localization of the remaining three human nuclear encoded iron sulphur protein (IP) subunits of complex I: the human IP fraction is completed". Biochemical and Biophysical Research Communications247 (3): 751–8. doi:10.1006/bbrc.1998.8882. PMID9647766.
Loeffen JL, Triepels RH, van den Heuvel LP, Schuelke M, Buskens CA, Smeets RJ et al. (Dec 1998). "cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase: human complex I cDNA characterization completed". Biochemical and Biophysical Research Communications253 (2): 415–22. doi:10.1006/bbrc.1998.9786. PMID9878551.
Triepels RH, Hanson BJ, van den Heuvel LP, Sundell L, Marusich MF, Smeitink JA et al. (Mar 2001). "Human complex I defects can be resolved by monoclonal antibody analysis into distinct subunit assembly patterns". The Journal of Biological Chemistry276 (12): 8892–7. doi:10.1074/jbc.M009903200. PMID11112787.
Murray J, Taylor SW, Zhang B, Ghosh SS, Capaldi RA (Sep 2003). "Oxidative damage to mitochondrial complex I due to peroxynitrite: identification of reactive tyrosines by mass spectrometry". The Journal of Biological Chemistry278 (39): 37223–30. doi:10.1074/jbc.M305694200. PMID12857734.
Ugalde C, Janssen RJ, van den Heuvel LP, Smeitink JA, Nijtmans LG (Mar 2004). "Differences in assembly or stability of complex I and other mitochondrial OXPHOS complexes in inherited complex I deficiency". Human Molecular Genetics13 (6): 659–67. doi:10.1093/hmg/ddh071. PMID14749350.
Vogel RO, Dieteren CE, van den Heuvel LP, Willems PH, Smeitink JA, Koopman WJ et al. (Mar 2007). "Identification of mitochondrial complex I assembly intermediates by tracing tagged NDUFS3 demonstrates the entry point of mitochondrial subunits". The Journal of Biological Chemistry282 (10): 7582–90. doi:10.1074/jbc.M609410200. PMID17209039.