NDUFS3 explained

NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial is an enzyme that in humans is encoded by the NDUFS3 gene on chromosome 11.^{[1] [2]} This gene encodes one of the iron-sulfur protein (IP) components of mitochondrial NADH:ubiquinone oxidoreductase (complex I). Mutations in this gene are associated with Leigh syndrome resulting from mitochondrial complex I deficiency.^[2]

Structure

The NDUFS3 gene encodes a protein subunit consisting of 263 amino acids. This protein is synthesized in the cytoplasm and then transported to the mitochondria via a signal peptide. Two mutations that occur in its highly conserved C-terminal region, T145I and R199W, are causally linked to Leigh syndrome and optic atrophy. Nonetheless, despite its crucial biological role, the human NDUFS3 remains structurally poorly understood.^[3]

Function

This gene encodes one of the iron-sulfur protein (IP) components of complex I.^[2] The 45-subunit NADH:ubiquinone oxidoreductase (complex I) is the first enzyme complex in the electron transport chain of mitochondria.^{[2] [4]} As a catalytic subunit, NDUFS3 plays a vital role in the proper assembly of complex I and is recruited to the inner mitochondrial membrane to form an early assembly intermediate with NDUFS2.^{[4] [5]} It initiates the assembly of complex I in the mitochondrial matrix.^[3]

Cleavage of NDUFS3 by GzmA has been observed to activate a programmed cell death pathway which results in mitochondrial dysfunction and reactive oxygen species (ROS) generation.^[6]

Clinical significance

Mutations in the NDUFS3 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.^{[7] [8]} 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.^[9] However, the majority of cases are caused by mutations in nuclear-encoded genes.^{[10] [11]} 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.^[12]

NDUFS3 has also been implicated in breast cancer and ductal carcinoma and, thus, may serve as a novel biomarker for tracking cancer progression and invasiveness.^[4]

See also

• NDUFS1

Further reading

• Dawson SJ, White LA . Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin . The Journal of Infection . 24 . 3 . 317–20 . May 1992 . 1602151 . 10.1016/S0163-4453(05)80037-4 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . Jan 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . Oct 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Loeffen J, van den Heuvel L, Smeets R, Triepels R, Sengers R, Trijbels F, Smeitink J . 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 Communications . 247 . 3 . 751–8 . Jun 1998 . 9647766 . 10.1006/bbrc.1998.8882 .
• Loeffen JL, Triepels RH, van den Heuvel LP, Schuelke M, Buskens CA, Smeets RJ, Trijbels JM, Smeitink JA . 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 . Dec 1998 . 9878551 . 10.1006/bbrc.1998.9786 .
• Hu RM, Han ZG, Song HD, Peng YD, Huang QH, Ren SX, Gu YJ, Huang CH, Li YB, Jiang CL, Fu G, Zhang QH, Gu BW, Dai M, Mao YF, Gao GF, Rong R, Ye M, Zhou J, Xu SH, Gu J, Shi JX, Jin WR, Zhang CK, Wu TM, Huang GY, Chen Z, Chen MD, Chen JL . Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning . Proceedings of the National Academy of Sciences of the United States of America . 97 . 17 . 9543–8 . Aug 2000 . 10931946 . 16901 . 10.1073/pnas.160270997 . 2000PNAS...97.9543H . free .
• Procaccio V, Lescuyer P, Bourges I, Beugnot R, Duborjal H, Depetris D, Mousson B, Montfort MF, Smeets H, De Coo R, Issartel JP . Human NDUFS3 gene coding for the 30-kDa subunit of mitochondrial complex I: genomic organization and expression . Mammalian Genome . 11 . 9 . 808–10 . Sep 2000 . 10967146 . 10.1007/s003350010160 . 6619646 .
• Triepels RH, Hanson BJ, van den Heuvel LP, Sundell L, Marusich MF, Smeitink JA, Capaldi RA . 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 . Mar 2001 . 11112787 . 10.1074/jbc.M009903200 . free . 2066/185667 . free .
• Book: Kim SH, Fountoulakis M, Dierssen M, Lubec G . 2001 . Protein Expression in Down Syndrome Brain . Decreased protein levels of complex I 30-kDa subunit in fetal Down syndrome brains . Journal of Neural Transmission. Supplementum . 61 . 109–16 . 11771736 . 10.1007/978-3-7091-6262-0_9 . 978-3-211-83704-7 .
• Bénit P, Slama A, Cartault F, Giurgea I, Chretien D, Lebon S, Marsac C, Munnich A, Rötig A, Rustin P . Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome . Journal of Medical Genetics . 41 . 1 . 14–7 . Jan 2004 . 14729820 . 1757256 . 10.1136/jmg.2003.014316 .
• Bourges I, Ramus C, Mousson de Camaret B, Beugnot R, Remacle C, Cardol P, Hofhaus G, Issartel JP . Structural organization of mitochondrial human complex I: role of the ND4 and ND5 mitochondria-encoded subunits and interaction with prohibitin . The Biochemical Journal . 383 . Pt. 3 . 491–9 . Nov 2004 . 15250827 . 1133742 . 10.1042/BJ20040256 .
• Huang G, Chen Y, Lu H, Cao X . Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-beta and retinoic acid-induced cancer cell death . Cell Death and Differentiation . 14 . 2 . 327–37 . Feb 2007 . 16826196 . 10.1038/sj.cdd.4402004 . free .
• Vogel RO, Dieteren CE, van den Heuvel LP, Willems PH, Smeitink JA, Koopman WJ, Nijtmans LG . Identification of mitochondrial complex I assembly intermediates by tracing tagged NDUFS3 demonstrates the entry point of mitochondrial subunits . The Journal of Biological Chemistry . 282 . 10 . 7582–90 . Mar 2007 . 17209039 . 10.1074/jbc.M609410200 . free . 2066/52607 . free .

Notes and References

1. Emahazion T, Beskow A, Gyllensten U, Brookes AJ . 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 . Nov 1998 . 9763677 . 10.1159/000015082 . 46818955 .
2. Web site: Entrez Gene: NDUFS3 NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase).
3. Jaokar. TM. Patil. DP. Shouche. YS. Gaikwad. SM. Suresh. CG. Human mitochondrial NDUFS3 protein bearing Leigh syndrome mutation is more prone to aggregation than its wild-type.. Biochimie. December 2013. 95. 12. 2392–403. 24028823. 10.1016/j.biochi.2013.08.032.
4. Suhane S, Berel D, Ramanujan VK . Biomarker signatures of mitochondrial NDUFS3 in invasive breast carcinoma . Biochemical and Biophysical Research Communications . 412 . 4 . 590–5 . Sep 2011 . 21867691 . 10.1016/j.bbrc.2011.08.003 . 3171595.
5. Saada A, Vogel RO, Hoefs SJ, van den Brand MA, Wessels HJ, Willems PH, Venselaar H, Shaag A, Barghuti F, Reish O, Shohat M, Huynen MA, Smeitink JA, van den Heuvel LP, Nijtmans LG . Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease . American Journal of Human Genetics . 84 . 6 . 718–27 . Jun 2009 . 19463981 . 10.1016/j.ajhg.2009.04.020 . 2694978.
6. Lieberman J . Granzyme A activates another way to die . Immunological Reviews . 235 . 1 . 93–104 . May 2010 . 20536557 . 10.1111/j.0105-2896.2010.00902.x . 2905780.
7. Kirby DM, Salemi R, Sugiana C, Ohtake A, Parry L, Bell KM, Kirk EP, Boneh A, Taylor RW, Dahl HH, Ryan MT, Thorburn DR . NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency . The Journal of Clinical Investigation . 114 . 6 . 837–45 . Sep 2004 . 15372108 . 10.1172/JCI20683 . 516258.
8. McFarland R, Kirby DM, Fowler KJ, Ohtake A, Ryan MT, Amor DJ, Fletcher JM, Dixon JW, Collins FA, Turnbull DM, Taylor RW, Thorburn DR . De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency . Annals of Neurology . 55 . 1 . 58–64 . Jan 2004 . 14705112 . 10.1002/ana.10787 . 21076359 .
9. Haack TB, Haberberger B, Frisch EM, Wieland T, Iuso A, Gorza M, Strecker V, Graf E, Mayr JA, Herberg U, Hennermann JB, Klopstock T, Kuhn KA, Ahting U, Sperl W, Wilichowski E, Hoffmann GF, Tesarova M, Hansikova H, Zeman J, Plecko B, Zeviani M, Wittig I, Strom TM, Schuelke M, Freisinger P, Meitinger T, Prokisch H . Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing . Journal of Medical Genetics . 49 . 4 . 277–83 . Apr 2012 . 22499348 . 10.1136/jmedgenet-2012-100846 . 3177674 .
10. Loeffen JL, Smeitink JA, Trijbels JM, Janssen AJ, Triepels RH, Sengers RC, van den Heuvel LP . Isolated complex I deficiency in children: clinical, biochemical and genetic aspects . Human Mutation . 15 . 2 . 123–34 . 2000 . 10649489 . 10.1002/(SICI)1098-1004(200002)15:2<123::AID-HUMU1>3.0.CO;2-P . 35579133 . free .
11. Triepels RH, Van Den Heuvel LP, Trijbels JM, Smeitink JA . Respiratory chain complex I deficiency . American Journal of Medical Genetics . 106 . 1 . 37–45 . 2001 . 11579423 . 10.1002/ajmg.1397 .
12. Robinson BH . Human complex I deficiency: clinical spectrum and involvement of oxygen free radicals in the pathogenicity of the defect . Biochimica et Biophysica Acta (BBA) - Bioenergetics . 1364 . 2 . 271–86 . May 1998 . 9593934 . 10.1016/s0005-2728(98)00033-4. free .