Skip to main content
SpringerLink
Log in

Manganese Superoxide Dismutase (MnSOD) and Its Importance in Mitochondrial Function and Cancer

  • Chapter
  • First Online:
Redox-Active Therapeutics

  • 1028 Accesses

Abstract

Mitochondria are vital metabolic centers in the cell, containing key enzymes for numerous metabolic pathways, such as the Krebs cycle, urea cycle, iron metabolism, fatty acid oxidation, and heme synthesis, to name a few. Mitochondria are the major site of oxygen consumption for use in oxidative phosphorylation to produce ATP, with reactive oxygen species (ROS) being produced as a by-product of oxygen metabolism. ROS can have deleterious effects on multiple mitochondria-centered activities, leading to the development of numerous diseases, including cancer. Manganese superoxide dismutase (MnSOD) is an essential antioxidant enzyme localized in mitochondria. MnSOD protects the cell from the harmful effects of ROS, in general, and guards against mitochondrial dysfunction, in particular. MnSOD plays a dual role in cancer development, acting as a tumor suppressor during early stages of carcinogenesis and facilitating cancer progression at later stages of development. A greater understanding of the role of MnSOD in preserving mitochondrial function can give important insights for the development of novel therapeutic strategies for the treatment of cancer and other diseases resulting from mitochondrial dysfunction.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Abaci N, Arikan M, Tansel T, Sahin N, Cakiris A, Pacal F, Sirma Ekmekci S, Gok E, Ustek D. Mitochondrial mutations in patients with congenital heart defects by next generation sequencing technology. Cardiol Young. 2015;25:705–11.

    Article  PubMed  Google Scholar 

  2. Abate C, Patel L, Rauscher III FJ, Curran T. Redox regulation of Fos and Jun DNA-binding activity in vitro. Science. 1990;249:1157–61.

    Article  CAS  PubMed  Google Scholar 

  3. Abello N, Kerstjens HAM, Postma DS, Bischoff R. Protein tyrosine nitration: selectivity, physicochemical and biological consequences, denitration, and proteomics methods for the identification of tyrosine-nitrated proteins. J Proteome Res. 2009;8:3222–38.

    Article  CAS  PubMed  Google Scholar 

  4. Adam-Vizi V, Chinopoulos C. Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol Sci. 2006;27:639–45.

    Article  CAS  PubMed  Google Scholar 

  5. Adams JM. Ways of dying: multiple pathways to apoptosis. Genes Dev. 2003;17:2481–95.

    Article  CAS  PubMed  Google Scholar 

  6. Afford S, Randhawa S. Demystified…Apoptosis. J Clin Pathol Mol Pathol. 2000;53:55–63.

    Article  CAS  Google Scholar 

  7. Ahles TA, Saykin AJ. Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer. 2007;7:192–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Aida Y, Maeyama S, Takakuwa T, Uchikoshi T, Endo Y, Suzuki K, Taniguchi N. Immunohistochemical expression of manganese superoxide dismutase in hepatocellular carcinoma, using a specific monoclonal antibody. J Gastroenterol. 1994;29:443–9.

    Article  CAS  PubMed  Google Scholar 

  9. Ajioka RS, Phillips JD, Kushner JP. Biosynthesis of heme in mammals. Biochim Biophys Acta. 2006;1763:723–36.

    Article  CAS  PubMed  Google Scholar 

  10. Albracht SPJ. The prosthetic groups in succinate dehydrogenase number and stoichiometry. Biochim Biophys Acta. 1980;612:11–28.

    Article  CAS  PubMed  Google Scholar 

  11. Albracht SPJ, Subramanian J. The number of Fe atoms in the iron-sulfur centers of the respiratory chain. Biochim Biophys Acta. 1977;462:36–48.

    Article  CAS  PubMed  Google Scholar 

  12. Allikmets R, Raskind WH, Hutchinson A, Scheuck ND, Dean M, Koeller DM. Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Hum Mol Genet. 1999;8:743–9.

    Article  CAS  PubMed  Google Scholar 

  13. Anderson S, Bankier AT, Barrell BG, de Bruijn MHL, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJH, Staden R, Young IG. Sequence and organization of the human mitochondrial genome. Nature. 1981;290:457–65.

    Article  CAS  PubMed  Google Scholar 

  14. Andreyev AY, Kushnareva YE, Starkov AA. Mitochondrial metabolism of reactive oxygen species. Biochemistry (Mosc). 2005;70:246–64.

    Article  CAS  Google Scholar 

  15. Baker PRS, Schopfer FJ, O’Donnell VB, Freeman BA. Convergence of nitric oxid and lipid signaling: anti-inflammatory nitro-fatty acids. Free Radic Biol Med. 2009;46:989–1003.

    Article  CAS  PubMed  Google Scholar 

  16. Bakthavatchalu V, Dey S, Xu Y, Noel T, Jungsuwadee P, Holley AK, Dhar SK, Batinic-Haberle I, St Clair DK. Manganese superoxide dismutase is a mitochondrial fidelity protein that protects Polgamma against UV-induced inactivation. Oncogene. 2012;31:2129–39.

    Article  CAS  PubMed  Google Scholar 

  17. Basu A, Castle VP, Bouziane M, Bhalla K, Haldar S. Crosstalk between extrinsic and intrainsic cell death pathways in pancreatic cancer: synergistic action of estrogen metabolite and ligands of death receptor family. Cancer Res. 2006;66:4309–18.

    Article  CAS  PubMed  Google Scholar 

  18. Batinic-Haberle I, Reboucas JS, Spasojevic I. Response to Rosenthal et al. Antioxid Redox Signal. 2011;14:1174–6.

    Article  CAS  Google Scholar 

  19. Batinic-Haberle I, Tovmasyan A, Roberts ER, Vujaskovic Z, Leong KW, Spasojevic I. SOD therapeutics: latest insights into their structure-activity relationships and impact on the cellular redox-based signaling pathways. Antioxid Redox Signal. 2014;20:2372–415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bauer G. Targeting extracellular ROS signaling of tumor cells. Anticancer Res. 2014;34:1467–82.

    CAS  PubMed  Google Scholar 

  21. Behrend L, Mohr A, Dick T, Zwacka RM. Manganese superoxide dismutase induces p53-dependent senescence in colorectal cancer cells. Mol Cell Biol. 2005;25:7758–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bekri S, Kispal G, Lange H, Fitzsimons E, Tolmie J, Lill R, Bishop DF. Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation. Blood. 2000;96:3256–64.

    CAS  PubMed  Google Scholar 

  23. Benov L, Batinic-Haberle I. A manganese porphyrin suppresses oxidative stress and extends the life span of streptozotocin-diabetic rats. Free Radic Res. 2005;39:81–8.

    Article  CAS  PubMed  Google Scholar 

  24. Biaglow JE, Miller RA. The thioredoxin reductase/thioredoxin system: novel redox targets for cancer therapy. Cancer Biol Ther. 2005;4:6–13.

    Article  CAS  PubMed  Google Scholar 

  25. Birch-Machin MA, Swalwell H. How mitochondria record the effects of UV exposure and oxidative stress using human skin as a model tissue. Mutagenesis. 2010;25:101–7.

    Article  CAS  PubMed  Google Scholar 

  26. Boffoli D, Scacco SC, Vergari R, Solarino G, Santacroce G, Papa S. Decline with age of the respiratory chain activity in human skeletal muscle. Biochim Biophys Acta. 1994;1226:73–82.

    Article  CAS  PubMed  Google Scholar 

  27. Boland ML, Chourasia AH, Macleod KF. Mitochondrial Dysfunction in Cancer. Front Oncol. 2013;3:292.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Boonstra J, Post JA. Molecular events associated with reactive oxygen species and cell cycle progression in mammalian cells. Gene. 2004;337:1–13.

    Article  CAS  PubMed  Google Scholar 

  29. Brandon M, Baldi P, Wallace DC. Mitochondrial mutations in cancer. Oncogene. 2006;25:4647–62.

    Article  CAS  PubMed  Google Scholar 

  30. Briere J-J, Favier J, Gimenez-Roqueplo A-P, Rustin P. Tricarboxylic acid cycle dysfunction as a cause of human diseases and tumor formation. Am J Physiol Cell Physiol. 2006;291:C1114–20.

    Article  CAS  PubMed  Google Scholar 

  31. Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu S-S. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol. 2004;287:817–33.

    Article  Google Scholar 

  32. Brown GC, Borutaite V. Inhibition of mitochondrial respiratory complex I by nitric oxide, peroxynitrite and S-nitrosothiols. Biochim Biophys Acta. 2004;1658:44–9.

    Article  CAS  PubMed  Google Scholar 

  33. Brown MS, Stemmer SM, Simon JH, Stears JC, Jones RB, Cagnoni PJ, Sheeder JL. White matter disease induced by high-dose chemotherapy: longitudinal study with MR imaging and proton spectroscopy. AJNR Am J Neuroradiol. 1998;19:217–21.

    CAS  PubMed  Google Scholar 

  34. Buettner GR, Ng CF, Wang M, Rodgers VGJ, Schafer FQ. A new paradigm: manganese superoxide dismutase influences the production of H2O2 in cells and thereby their biological state. Free Radic Biol Med. 2006;41:1338–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bulua AC, Simon A, Maddipati R, Pelletier M, Park H, Kim K-Y, Sack MN, Kastner DL, Siegel RM. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med. 2011;208:519–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cai Z, Yan LJ. Protein oxidative modifications: beneficial roles in disease and health. J Biochem Pharmacol Res. 2013;1:15–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Cantu D, Schaack J, Patel M. Oxidative inactivation of mitochondrial aconitase results in iron and H2O2-mediated neurotoxicity in rat primary mesencephalic cultures. PLoS One. 2009;4, e7095.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Canuto RA, Biocca ME, Muzio G, Dianzani MU. Fatty acid composition of phospholipids in mitochondria and microsomes during diethylnitrosamine carcinogenesis in rat liver. Cell Biochem Funct. 1989;7:11–9.

    Article  CAS  PubMed  Google Scholar 

  39. Carl GF, Keen CL, Gallagher BB, Clegg MS, Littleton WH, Flannery DB, Hurley LS. Association of low blood manganese concentrations with epilepsy. Neurology. 1986;36:1584–7.

    Article  CAS  PubMed  Google Scholar 

  40. Case AJ, McGill JL, Tygrett LT, Shirasawa T, Spitz DR, Waldschmidt TJ, Legge KL, Domann FE. Elevated mitochondrial superoxide disrupts normal T cell development, impairing adaptive immune response to an influenza challenge. Free Radic Biol Med. 2011;50:448–58.

    Article  CAS  PubMed  Google Scholar 

  41. Cassina A, Radi R. Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport. Arch Biochem Biophys. 1996;328:309–16.

    Article  CAS  PubMed  Google Scholar 

  42. Castro L, Rodriquez M, Radi R. Aconitase is readily inactivated by peroxynitrite, but not by its precursor, nitric oxide. J Biol Chem. 1994;269:29409–15.

    CAS  PubMed  Google Scholar 

  43. Cavadini P, Biasiotto G, Poli M, Levi S, Verardi R, Zanella I, Derosas M, Ingrassia R, Corrado M, Arosio P. RNA silencing of the mitochondrial ABCB7 transporter in HeLa cells causes an iron-deficient phenotype with mitochondrial iron overload. Blood. 2007;109:3552–9.

    Article  CAS  PubMed  Google Scholar 

  44. Celardo I, Martins LM, Gandhi S. Unravelling mitochondrial pathways to Parkinson’s disease. Br J Pharmacol. 2014;171:1943–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chang T-S, Cho C-S, Park S, Yu S, Kang SW. Peroxiredoxin III, a mitochondrion-specific peroxidase, regulate apoptotic signaling by mitochondria. J Biol Chem. 2004;279:41975–84.

    Article  CAS  PubMed  Google Scholar 

  46. Chelikani P, Fita I, Loewen PC. Diversity of structures and properties among catalases. Cell Mol Life Sci. 2004;61:192–208.

    Article  CAS  PubMed  Google Scholar 

  47. Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL, Lesnefsky EJ. Production of reactive oxygen species by mitochondria: central role of complex III. J Biol Chem. 2003;278:36027–31.

    Article  CAS  PubMed  Google Scholar 

  48. Chen XJ, Butow RA. The organization and inheritance of the mitochondrial genome. Nat Rev Genet. 2005;6:815–25.

    Article  CAS  PubMed  Google Scholar 

  49. Chen Y-R, Chen C-L, Zhang L, Green-Church KB, Zweier JL. Superoxide generation from mitochondrial NADH dehydrogenase induces self-inactivation with specific protein radical formation. J Biol Chem. 2005;280:37339–48.

    Article  CAS  PubMed  Google Scholar 

  50. Chen YR, Chen CL, Liu X, Li H, Zweier JL, Mason RP. Involvement of protein radical, protein aggregation, and effects on NO metabolism in the hypochlorite-mediated oxidation of mitochondrial cytochrome c. Free Radic Biol Med. 2004;37:1591–603.

    Article  CAS  PubMed  Google Scholar 

  51. Chen Z, Siu B, Ho YS, Vincent R, Chua CC, Hamdy RC, Chua BH. Overexpression of MnSOD protects against myocardial ischemia/reperfusion injury in transgenic mice. J Mol Cell Cardiol. 1998;30:2281–9.

    Article  CAS  PubMed  Google Scholar 

  52. Chinta SJ, Andersen JK. Nitrosylation and nitration of mitochondrial complex I in Parkinson’s disease. Free Radic Res. 2011;45:53–8.

    Article  CAS  PubMed  Google Scholar 

  53. Choi JH, Kim TN, Kim S, Baek SH, Kim JH, Lee SR, Kim JR. Overexpression of mitochondrial thioredoxin reductase and peroxiredoxin III in hepatocellular carcinoma. Anticancer Res. 2002;22:3331–5.

    CAS  PubMed  Google Scholar 

  54. Chuang T-C, Liu J-Y, Lin C-T, Tang Y-T, Yeh M-H, Chang S-C, Li J-W, Kao M-C. Human manganese superoxide dismutase suppresses HER2/neu-mediated breast cancer malignancy. FEBS Lett. 2007;581:4443–9.

    Article  CAS  PubMed  Google Scholar 

  55. Church SL, Grant JW, Ridnour LA, Oberley LW, Swanson PE, Meltzer PS, Trent JM. Increased manganese superoxide dismutase expression suppresses the malignant phenotype of human melanoma cells. Proc Natl Acad Sci U S A. 1993;90:3113–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. Crit Care Med. 2009;37:291–304.

    Article  CAS  PubMed  Google Scholar 

  57. Claypool SM. Cardiolipin, a critical determinant of mitochondrial carrier protein assembly and function. Biochim Biophys Acta. 2009;1788:2059–68.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Connor KM, Hempel N, Nelson KK, Dabiri G, Gamarra A, Balarmino J, van de Water L, Mian BM, Melendez JA. Manganese superoxide dismutase enhances the invasive and migratory activity of tumor cells. Cancer Res. 2007;67:10260–7.

    Article  CAS  PubMed  Google Scholar 

  59. Converso DP, Taille C, Carreras C, Jaitovich A, Poderoso JJ, Boczkowski J. HO-1 is located in liver mitochondria and modulates mitochondrial heme content and metabolism. FASEB J. 2006;20:E482–92.

    Article  Google Scholar 

  60. Copin J-C, Gasche Y, Chan PH. Overexpression of copper/zinc superoxide dismutase does not prevent neonatal lethality in mutant mice that lack manganese superoxide dismutase. Free Radic Biol Med. 2000;28:1571–6.

    Article  CAS  PubMed  Google Scholar 

  61. Cortopassi G, Wang E. Modelling the effects of age-related mtDNA mutation accumulation; Complex I deficiency, superoxide and cell death. Biochim Biophys Acta. 1995;1271:171–6.

    Article  PubMed  Google Scholar 

  62. Cullen JJ, Weydert C, Hinkhouse MM, Ritchie J, Domann FE, Spitz D, Oberley LW. The role of manganese superoxide dismutase in the growth of pancreatic adenocarcinoma. Cancer Res. 2003;63:1297–303.

    CAS  PubMed  Google Scholar 

  63. Daosukho C, Ittarat W, Lin S-M, Sawyer DB, Kiningham K, Lien Y-C, St. Clair DK. Induction of manganese superoxide dismutase (MnSOD) mediates cardioprotective effect of tamoxifen (TAM). J Mol Cell Cardiol. 2005;39:792–803.

    Article  CAS  PubMed  Google Scholar 

  64. Daosukho C, Kiningham K, Kasarskis EJ, Ittarat W, St. Clair DK. Tamoxifen enhancement of TNF-α induced MnSOD expression: modulation of NF-κB dimerization. Oncogene. 2002;21:3603–10.

    Article  CAS  PubMed  Google Scholar 

  65. Dasgupta J, Subbaram S, Connor KM, Rodriguez AM, Tirosh O, Beckman JS, Jourd’Heuil D, Melendez JA. Manganese superoxide dismutase protects from TNF-α-induced apoptosis by increasing the steady-state production of H2O2. Antioxid Redox Signal. 2006;8:1295–305.

    Article  CAS  PubMed  Google Scholar 

  66. Davis CA, Hearn AS, Fletcher B, Bickford J, Garcia JE, Leveque V, Melendez JA, Silverman DN, Zucali J, Agarwal A, Nick HS. Potent anti-tumor effects of an active site mutant of human manganese-superoxide dismutase. Evolutionary conservation of product inhibition. J Biol Chem. 2004;279:12769–76.

    Article  CAS  PubMed  Google Scholar 

  67. Dhar SK, St Clair DK. Manganese superoxide dismutase regulation and cancer. Free Radic Biol Med. 2012;52:2209–22.

    Article  CAS  PubMed  Google Scholar 

  68. Dhar SK, Tangpong J, Chaiswing L, Oberley TD, St. Clair DK. Manganese superoxide dismutase is a p53-regulated gene that switches cancers between early and advanced stages. Cancer Res. 2011;71:6684–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Dhar SK, Xu Y, Chen Y, St. Clair DK. Specificity protein 1-dependent p53-mediated suppression of human manganese superoxide dismutase gene expression. J Biol Chem. 2006;281:21698–709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Dhar SK, Xu Y, St. Clair DK. Nuclear factor κB- and specificity protein 1-dependent p53-mediated bi-directional regulation of the human manganese superoxide dismutase gene. J Biol Chem. 2010;285:9835–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Dhingra S, Feng W, Brown RE, Zhou Z, Khoury T, Zhang R, Tan D. Clinicopathologic significance of putative stem cell markers, CD44 and nestin, in gastric adenocarcinoma. Int J Clin Exp Pathol. 2011;4:733–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Dlaskova A, Hlavata L, Jezek P. Oxidative stress caused by blocking of mitochondrial complex I H+ pumping as a link in aging/disease vicious cycle. Int J Biochem Cell Biol. 2008;40:1792–805.

    Article  CAS  PubMed  Google Scholar 

  73. Dominic EA, Ramezani A, Anker SD, Verma M, Mehta N, Rao M. Mitochondrial cytopathies and cardiovascular disease. Heart. 2014;100:611–8.

    Article  CAS  PubMed  Google Scholar 

  74. Dostert C, Petrilli V, van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008;320:674–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Drahota Z, Chowdhury SKR, Floryk D, Mracek T, Wilhelm J, Rauchova H, Lenaz G, Houstek J. Glycerophosphate-dependent hydrogen peroxide production by brown adipose tissue mitochondria and its activation by ferricyanide. J Bioenerg Biomembr. 2002;34:105–13.

    Article  CAS  PubMed  Google Scholar 

  76. Droge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002;82:47–95.

    Article  CAS  PubMed  Google Scholar 

  77. Duttaroy A, Paul A, Kundu M, Belton A. A Sod2 null mutation confers severely reduced adult life span in drosophila. Genetics. 2003;165:2295–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Eaton JW, Qian M. Molecular bases of cellular iron toxicity. Free Radic Biol Med. 2002;32:833–40.

    Article  CAS  PubMed  Google Scholar 

  79. Epperly MW, Sikora CA, DeFilippi SJ, Gretton JE, Zhan Q, Kufe DW, Greenberger JS. Manganese superoxide dismutase (SOD2) inhibits radiation-induced apoptosis by stabilization of the mitochondrial membrane. Radiat Res. 2002;157:568–77.

    Article  CAS  PubMed  Google Scholar 

  80. Epperly MW, Tyurina YY, Nie S, Niu YY, Zhang X, Kagan VE, Greenberger JS. MnSOD-plasmid liposome gene therapy decreases ionizing irradiation-induced lipid peroxidation of the esophagus. In Vivo. 2005;19:997–1004.

    CAS  PubMed  Google Scholar 

  81. Esworthy RS, Ho Y-S, Chu F-F. The Gpx1 gene encodes mitochondrial glutathione peroxidase in the mouse liver. Arch Biochem Biophys. 1997;340:59–63.

    Article  CAS  PubMed  Google Scholar 

  82. Fernandez MG, Troiano L, Moretti L, Nasi M, Pinti M, Salvioli S, Dobrucki J, Cossarizza A. Early changes in intramitochondrial cardiolipin distribution during apoptosis. Cell Growth Differ. 2002;13:449–55.

    CAS  Google Scholar 

  83. Fillmore N, Mori J, Lopaschuk GD. Mitochondrial fatty acid oxidation alterations in heart failure, ischaemic heart disease and diabetic cardiomyopathy. Br J Pharmacol. 2014;171:2080–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Fojta M, Kubicarova T, Vojtesek B, Palecek E. Effect of p53 protein redox states on binding to supercoiled and linear DNA. J Biol Chem. 1999;274:25749–55.

    Article  CAS  PubMed  Google Scholar 

  85. Folz RJ, Crapo JD. Extracellular superoxide dismutase (SOD3): tissue-specific expression, genomic characterization, and computer-assisted sequence analysis of the human EC SOD gene. Genomics. 1994;22:162–71.

    Article  CAS  PubMed  Google Scholar 

  86. Fong K-L, McCay PB, Poyer JL. Evidence for superoxide-dependent reduction of Fe3+ and its role in enzyme-generated hydroxyl radical formation. Chem Biol Interact. 1976;15:77–89.

    Article  CAS  PubMed  Google Scholar 

  87. Forman HJ, Fukuto JM, Torres M. Redox signaling: thiol chemistry defines which reactive oxygen and nitrogen species can act as second messengers. Am J Physiol Cell Physiol. 2004;287:C246–56.

    Article  CAS  PubMed  Google Scholar 

  88. Forman HJ, Kennedy J. Superoxide production and electron transport in mitochondrial oxidation of dihydroorotic acid. J Biol Chem. 1975;250:4322–6.

    CAS  PubMed  Google Scholar 

  89. Forman HJ, Kennedy J. Dihydroorotate-dependent superoxide production in rat brain and liver: a function of the primary dehydrogenase. Arch Biochem Biophys. 1976;173:219–24.

    Article  CAS  PubMed  Google Scholar 

  90. Frankel D, Mehindate K, Schipper HM. Role of heme oxygenase-1 in the regulation of manganese superoxide dismutase gene expression in oxidatively-challenged astroglia. J Cell Physiol. 2000;185:80–6.

    Article  CAS  PubMed  Google Scholar 

  91. Fridovich I. The biology of oxygen radicals. Science. 1978;201:875–80.

    Article  CAS  PubMed  Google Scholar 

  92. Fridovich I. Superoxide dismutases. An adaptation to a paramagnetic gas. J Biol Chem. 1989;264:7761–4.

    CAS  PubMed  Google Scholar 

  93. Fridovich I. Superoxide radical and superoxide dismutases. Annu Rev Biochem. 1995;64:97–112.

    Article  CAS  PubMed  Google Scholar 

  94. Friedland-Leuner K, Stockburger C, Denzer I, Eckert GP, Müller WE. Chapter Seven—Mitochondrial dysfunction: cause and consequence of Alzheimer’s Disease. In: Heinz DO editor. Progress in molecular biology and translational science. Academic; 2014. pp. 183–210.

    Google Scholar 

  95. Fry M, Green DE. Cardiolipin requirement for electron transfer in complex I and III of the mitochondrial respiratory chain. J Biol Chem. 1981;256:1874–80.

    CAS  PubMed  Google Scholar 

  96. Galanis A, Pappa A, Giannakakis A, Lanitis E, Dangaj D, Sandaltzopoulos R. Reactive oxygen species and HIF-1 signaling in cancer. Cancer Lett. 2008;266:12–20.

    Article  CAS  PubMed  Google Scholar 

  97. Galeotti T, Wohlrab H, Borrello S, De Leo ME. Messenger RNA for manganese and copper-zinc superoxide dismutases in hepatomas: correlation with degree of differentiation. Biochem Biophys Res Commun. 1989;165:581–9.

    Article  CAS  PubMed  Google Scholar 

  98. Garcia-Ramirez M, Francisco G, Garcia-Arumi E, Hernandez C, Martinez R, Andreu AL, Simo R. Mitochondrial DNA oxidation and manganese superoxide dismutase activity in peripheral blood mononuclear cells from type 2 diabetic patients. Diabetes Metab. 2008;34:117–24.

    Article  CAS  PubMed  Google Scholar 

  99. Gardner PR. Superoxide-driven aconitase FE-S center cycling. Biosci Rep. 1997;17:33–42.

    Article  CAS  PubMed  Google Scholar 

  100. Gardner PR, Raineri I, Epstein LB, White CW. Superoxide radical and iron modulate aconitase activity in mammalian cells. J Biol Chem. 1995;270:13399–405.

    Article  CAS  PubMed  Google Scholar 

  101. Garrett TA, Kordestani R, Raetz CRH. Quantification of cardiolipin by liquid chromatography-electrospray ionization mass spectrometry. In: Alen Brix H, editor. Methods in Enzymology. Amsterdam: Elsevier; 2007.

    Google Scholar 

  102. Garrido N, Griparic L, Jokitalo E, Wartiovaara J, van der Bliek AM, Spelbrink JN. Composition and dynamics of human mitochondrial nucleoids. Mol Biol Cell. 2003;14:1583–96.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  103. Gaude E, Frezza C. Defects in mitochondrial metabolism and cancer. Cancer Metab. 2014;2:10.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Genova ML, Ventura B, Giuliano G, Bovina C, Formiggini G, Castelli GP, Lenaz G. The site of production of superoxide radical in mitochondrial complex I is not a bound ubisemiquinone but presumably iron-sulfur cluster N2. FEBS Lett. 2001;505:364–8.

    Article  CAS  PubMed  Google Scholar 

  105. Gonzalez F, Schug ZT, Houtkooper RH, MacKenzie ED, Brooks DG, Wanders RJA, Petit PX, Vaz FM, Gottlieb E. Cardiolipin provides an essential activating platform for caspase-8 on mitochondria. J Cell Biol. 2008;183:681–96.

    Article  CAS  Google Scholar 

  106. Goossens V, Grooten J, De Vos K, Fiers W. Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity. Proc Natl Acad Sci U S A. 1995;92:8115–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013;12:931–47.

    Article  CAS  PubMed  Google Scholar 

  108. Graziewicz MA, Day BJ, Copeland WC. The mitochondrial DNA polymerase as a target of oxidative damage. Nucleic Acids Res. 2002;30:2817–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Green DR, Reed JC. Mitochondria and apoptosis. Science. 1998;281:1309–12.

    Article  CAS  PubMed  Google Scholar 

  110. Gregory EM, Fridovich I. Oxygen toxicity and the superoxide dismutase. J Bacteriol. 1973;114:1193–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Gregory EM, Goscin SA, Fridovich I. Superoxide dismutase and oxygen toxicity in a eukaryote. J Bacteriol. 1974;117:456–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Grivennikova VG, Vinogradov AD. Generation of superoxide by the mitochondrial Complex I. Biochim Biophys Acta. 2006;1757:553–61.

    Article  CAS  PubMed  Google Scholar 

  113. Guda P, Guda C, Subramaniam S. Reconstruction of pathways associated with amino acid metabolism in human mitochondria. Genomics Proteomics Bioinformatics. 2007;5:166–76.

    Article  CAS  PubMed  Google Scholar 

  114. Gulbins E, Dreschers S, Bock J. Role of mitochondria in apoptosis. Exp Physiol. 2003;88:85–90.

    Article  CAS  PubMed  Google Scholar 

  115. Hainaut P, Milner J. Redox modulation of p53 conformation and sequence-specific DNA binding in vitro. Cancer Res. 1993;53:4469–73.

    CAS  PubMed  Google Scholar 

  116. Han D, Canali R, Garcia J, Aguilera R, Gallaher TK, Cadenas E. Sites and mechanisms of aconitase inactivation by peroxynitrite: modulation by citrate and glutathione. Biochemistry. 2005;44:11986–96.

    Article  CAS  PubMed  Google Scholar 

  117. Hanukoglu I. Antioxidant protective mechanisms against reactive oxygen species (ROS) generated by mitochondrial P450 systems in steroidogenic cells. Drug Metab Rev. 2006;38:171–96.

    Article  CAS  PubMed  Google Scholar 

  118. Hanukoglu I, Rapoport R, Weiner L, Sklan D. Electron leakage from the mitochondrial NADPH-adrenodoxin reductase-adrenodoxin-P450scc (cholesterol side chain cleavage) system. Arch Biochem Biophys. 1993;305:489–98.

    Article  CAS  PubMed  Google Scholar 

  119. Hauff KD, Hatch GM. Cardiolipin metabolism and Barth syndrome. Prog Lipid Res. 2006;45:91–101.

    Article  CAS  PubMed  Google Scholar 

  120. Hausladen A, Fridovich I. Superoxide and peroxynitrite inactivate aconitases, but nitric oxide does not. J Biol Chem. 1994;269:29405–8.

    CAS  PubMed  Google Scholar 

  121. Hempel N, Carrico PM, Melendez JA. Manganese superoxide dismutase (Sod2) and redox-control of signaling events that drive metastasis. Anticancer Agents Med Chem. 2011;11:191–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Herrero A, Barja G. Localization of the site of oxygen radical generation inside the complex I of heart and nonsynaptic brain mammalian mitochondria. J Bioenerg Biomembr. 2000;32:609–15.

    Article  CAS  PubMed  Google Scholar 

  123. Hirose K, Longo DI, Oppenheim JJ, Matsushima K. Overexpression of mitochondrial manganese superoxide dismutase promotes the survival of tumor cells exposed to interleukin-1, tumor necrosis factor, selected anticancer drugs, and ionizing radiation. FASEB J. 1993;7:361–8.

    CAS  PubMed  Google Scholar 

  124. Hjalmarsson K, Marklund SL, Engstrom A, Edlund T. Isolation and sequence of complimentary DNA encoding human extracellular superoxide dismutase. Proc Natl Acad Sci U S A. 1987;84:6340–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Ho JC-m, Zheng S, Comhair SA, Farver C, Erzurum SC. Differential expression of manganese superoxide dismutase and catalase in lung cancer. Cancer Res. 2001;61:8578–85.

    CAS  Google Scholar 

  126. Holley AK, Bakthavatchalu V, Velez-Roman JM, St Clair DK. Manganese superoxide dismutase: guardian of the powerhouse. Int J Mol Sci. 2011;12:7114–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Holley AK, Kiningham KK, Spitz DR, Edwards DP, Jenkins JT, Moore MR. Progestin stimulation of manganese superoxide dismutase and invasive properties in T47D human breast cancer cells. J Steroid Biochem Mol Biol. 2009;117:23–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Houten SM, Wanders RJA. A general introduction to the biochemistry of mitochondrial fatty acid β-oxidation. J Inherit Metab Dis. 2010;33:469–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Hoye AT, Davoren JE, Wipf P, Fink MP, Kagan VE. Targeting mitochondria. Acc Chem Res. 2008;41:87–97.

    Article  CAS  PubMed  Google Scholar 

  130. Hsu CC, Lee HC, Wei YH. Mitochondrial DNA alterations and mitochondrial dysfunction in the progression of hepatocellular carcinoma. World J Gastroenterol. 2013;19:8880–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Hu H, Luo M-l, X-l D, Feng Y-B, Zhang Y, Shen X-M, Xu X, Cai Y, Y-l H, Wang M-R. Up-regulated manganese superoxide dismutase expression increases apoptosis resistance in human esophageal squamous cell carcinomas. Chin Med J. 2007;120:2092–8.

    CAS  PubMed  Google Scholar 

  132. Hu Y, Rosen DG, Zhou Y, Feng L, Yang G, Liu J, Huang P. Mitochondrial manganese-superoxide dismutase expression in ovarian cancer: role in cell proliferation and response to oxidative stress. J Biol Chem. 2005;280:39485–92.

    Article  CAS  PubMed  Google Scholar 

  133. Huie RE, Padmaja S. The reaction of NO with superoxide. Free Radic Res Commun. 1993;18:195–9.

    Article  CAS  PubMed  Google Scholar 

  134. Hutson SM, Fenstermacher D, Mahar C. Role of mitochondrial transamination in branched chain amino acid metabolism. J Biol Chem. 1988;263:3618–25.

    CAS  PubMed  Google Scholar 

  135. Ikegami T, Suzuki Y-I, Shimizu T, Isono K-I, Koseki H, Shirasawa T. Model mice for tissue-specific deletion of the manganese superoxide dismutase (MnSOD) gene. Biochem Biophys Res Commun. 2002;296:729–36.

    Article  CAS  PubMed  Google Scholar 

  136. Inagaki M, Yoshikawa E, Matsuoka Y, Sugawara Y, Nakano T, Akechi T, Wada N, Imoto S, Murakami K, Uchitomi Y, Group TBCSBMD. Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer. 2007;109:146–56.

    Article  PubMed  Google Scholar 

  137. Indo HP, Davidson M, Yen H-C, Suenaga S, Tomita K, Nishii T, Higuchi M, Koga Y, Ozawa T, Majima HJ. Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage. Mitochondrion. 2007;7:106–18.

    Article  CAS  PubMed  Google Scholar 

  138. Izutani R, Asano S, Imano M, Kuroda D, Kato M, Ohyanagi H. Expression of manganese superoxide dismutase in esophageal and gastric cancers. J Gastroenterol. 1998;33:816–22.

    Article  CAS  PubMed  Google Scholar 

  139. Jahnke VE, Sabido O, Defour A, Castells J, Lefai E, Roussel D, Freyssenet D. Evidence for mitochondrial respiratory deficiency in rat rhabdomyosarcoma cells. PLoS One. 2010;5, e8637.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Jang YC, Perez VI, Song W, Lustgarten MS, Salmon AB, Mele J, Qi W, Liu Y, Liang H, Chaudhuri A, Ikeno Y, Epstein CJ, Van Remmen H, Richardson A. Overexpression of Mn superoxide dismutase does not increase life span in mice. J Gerontol A Biol Sci Med Sci. 2009;64A:1114–25.

    Article  CAS  PubMed Central  Google Scholar 

  141. Janssen AML, Bosman CB, van Duijn W, Oostendorp-van de Ruit MM, Kubben FJGM, Griffioen G, Lamers BBHW, van Krieken JHJM, van de Velde CJH, Verspaget HW. Superoxide dismutases in gastric and esophageal cancer and the prognostic impact in gastric cancer. Clin Cancer Res. 2000;6:3183–92.

    CAS  PubMed  Google Scholar 

  142. Jiralerspong S, Ge B, Hudson TJ, Pandolfo M. Manganese superoxide dismutase induction by iron is impaired in Friedreich ataxia cells. FEBS Lett. 2001;509:101–5.

    Article  CAS  PubMed  Google Scholar 

  143. Joshi G, Sultana R, Tangpong J, Cole MP, St. Clair DK, Vore M, Estus S, Butterfield DA. Free radical mediated oxidative stress and toxic side effects in brain induced by the anticancer drug adriamycin: insight into chemobrain. Free Radic Res. 2005;29:1147–54.

    Article  CAS  Google Scholar 

  144. Kabe Y, Ando K, Hirao S, Yoshida M, Handa H. Redox regulation of NF-kappaB activation: distinct redox regulation between the cytoplasm and the nucleus. Antioxid Redox Signal. 2005;7:395–403.

    Article  CAS  PubMed  Google Scholar 

  145. Kang D, Hamasaki N. Alterations of mitochondrial DNA in common diseases and disease states: aging, neurodegeneration, heart failure, diabetes, and cancer. Curr Med Chem. 2005;12:429–41.

    Article  CAS  PubMed  Google Scholar 

  146. Kang YJ, Sun X, Chen Y, Zhou Z. Inhibition of doxorubicin chronic toxicity in catalase-overexpressing transgenic mouse hearts. Chem Res Toxicol. 2002;15:1–6.

    Article  PubMed  CAS  Google Scholar 

  147. Kattan Z, Minig V, Leroy P, Dauca M, Becuwe P. Role of manganese superoxide dismtuase on growth and invasive properties of human estrogen-independent breast cancer cells. Breast Cancer Res Treat. 2008;108:203–15.

    Article  CAS  PubMed  Google Scholar 

  148. Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol. 2009;21:317–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Kazi TG, Afridi HI, Kazi N, Jamali MK, Arain MB, Jalbani N, Kandhro GA. Copper, chromium, manganese, iron, nickel, and zinc levels in biological samples of diabetes mellitus patients. Biol Trace Elem Res. 2008;122:1–18.

    Article  CAS  PubMed  Google Scholar 

  150. Keele Jr BB, McCord JM, Fridovich I. Superoxide dismutase from Escherichia coli B. A new manganese-containing enzyme. J Biol Chem. 1970;245:6176–81.

    CAS  PubMed  Google Scholar 

  151. Keeney PM, Xie J, Capaldi RA, Bennett Jr JP. Parkinson’s disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci. 2006;26:5256–64.

    Article  CAS  PubMed  Google Scholar 

  152. Keller JN, Kindy MS, Holtsberg FW, St. Clair DK, Yen H-C, Germeyer A, Steiner SM, Bruce-Keller AJ, Hutchins JB, Mattson MP. Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. J Neurosci. 1998;18:687–97.

    CAS  PubMed  Google Scholar 

  153. Kelner MJ, Montoya MA. Structural organization of the human glutathione reductase gene: determination of correct cDNA sequence and identification of a mitochondrial leader sequence. Biochem Biophys Res Commun. 2000;269:366–8.

    Article  CAS  PubMed  Google Scholar 

  154. Khoshjou F, Dadras F. Mitochondrion and its role in diabetic nephropathy. Iran J Kidney Dis. 2014;8:355–8.

    PubMed  Google Scholar 

  155. Kiebish MA, Han X, Cheng H, Chuang JH, Seyfried TN. Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: lipidomic evidence supporting the Warburg theory of cancer. J Lipid Res. 2008;49:2545–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Kienhofer J, Haussler DJF, Ruckelshausen F, Muessig E, Weber K, Pimentel D, Ullrich V, Burkle A, Bachschmid MM. Association of mitochondrial antioxidant enzymes with mitochondrial DNA as integral nucleoid constituents. FASEB J. 2009;23:2034–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Kiningham KK, Oberley TD, Lin S-M, Mattingly CA, St. Clair DK. Overexpression of manganese superoxide dismutase protects against mitochondrial-initiated poly(ADP-ribose) polymerase-mediated cell death. FASEB J. 1999;13:1601–10.

    CAS  PubMed  Google Scholar 

  158. Kiningham KK, St. Clair DK. Overexpression of manganese superoxide dismutase selectively modulates the activity of Jun-associated transcription factors in fibrosarcoma cells. Cancer Res. 1997;57:5265–71.

    CAS  PubMed  Google Scholar 

  159. Klivenyi P, St Clair D, Wermer M, Yen HC, Oberley T, Yang L, Flint BM. Manganese superoxide dismutase overexpression attenuates MPTP toxicity. Neurobiol Dis. 1998;5:253–8.

    Article  CAS  PubMed  Google Scholar 

  160. Koehler CM, Beverley KN, Leverich EP. Redox pathways of the mitochondrion. Antioxid Redox Signal. 2006;8:813–22.

    Article  CAS  PubMed  Google Scholar 

  161. Kowluru RA, Kowluru V, Xiong Y, Ho YS. Overexpression of mitochondrial superoxide dismutase in mice protects the retina from diabetes-induced oxidative stress. Free Radic Biol Med. 2006;41:1191–6.

    Article  CAS  PubMed  Google Scholar 

  162. Kushnareva Y, Murphy AN, Andreyev A. Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P)+ oxidation-reduction state. Biochem J. 2002;368:545–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Kwak HB, Lee Y, Kim JH, Van Remmen H, Richardson AG, Lawler JM. MnSOD Overexpression reduces fibrosis and pro-apoptotic signaling in the aging mouse heart. J Gerontol A Biol Sci Med Sci. 2015;70(5):533–44.

    Article  PubMed  Google Scholar 

  164. Landriscina M, Remiddi F, Ria F, Palazzotti B, De Leo ME, Iacoangeli M, Rosselli R, Scerrati M, Galeotti T. The level of MnSOD is directly correlated with grade of brain tumours of neuroepithelial origin. Br J Cancer. 1996;74:1877–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Larosche I, Letteron P, Berson A, Fromenty B, Huang T-T, Moreau R, Pessayre D, Mansouri A. Hepatic mitochondrial DNA depletion after an alcohol binge in mice: probable role of peroxynitrite and modulation by manganese superoxide dismutase. J Pharmacol Exp Ther. 2010;332:886–97.

    Article  CAS  PubMed  Google Scholar 

  166. Lebovitz RM, Zhang H, Vogel H, Cartwright Jr J, Dionne L, Lu N, Huang S, Matzuk MM. Neurodegeneration, mycardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice. Proc Natl Acad Sci U S A. 1996;93:9782–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Lee HC, Huang KH, Yeh TS, Chi CW. Somatic alterations in mitochondrial DNA and mitochondrial dysfunction in gastric cancer progression. World J Gastroenterol. 2014;20:3950–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Lee S-M, Lee Y-S, Choi J-H, Park S-G, Choi I-W, Joo Y-D, Lee W-S, Lee J-N, Choi I, Seo S-K. Tryptophan metabolite 3-hydroxyanthranilic acid selectively induces activated T cell death via intracellular GSH depletion. Immunol Lett. 2010;132:53–60.

    Article  CAS  PubMed  Google Scholar 

  169. Lee S-R, Kim J-R, Kwon K-S, Yoon HW, Levine RL, Ginsburg A, Rhee SG. Molecular cloning and characterization of a mitochondrial selenocysteine-containing thioredoxin reductase from rat liver. J Biol Chem. 1999;274:4722–34.

    Article  CAS  PubMed  Google Scholar 

  170. Legros F, Malka F, Frachon P, Lombes A, Rojo M. Organization and dynamics of human mitochondrial DNA. J Cell Sci. 2004;117:2653–62.

    Article  CAS  PubMed  Google Scholar 

  171. Lemarie A, Grimm S. Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer. Oncogene. 2011;30(38):3985–4003.

    Article  CAS  PubMed  Google Scholar 

  172. Lenaz G. The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology. IUBMB Life. 2001;52:159–64.

    Article  CAS  PubMed  Google Scholar 

  173. Lesnefsky EJ, Minkler P, Hoppel CL. Enhanced modification of cardiolipin during ischemia in the aged heart. J Mol Cell Cardiol. 2009;46:1008–15.

    Article  CAS  PubMed  Google Scholar 

  174. Levi S, Rovida E. The role of iron in mitochondrial function. Biochim Biophys Acta. 2009;1790:629–36.

    Article  CAS  PubMed  Google Scholar 

  175. Levine RL, Stadtman ER. Oxidative modification of proteins during aging. Exp Gerontol. 2001;36:1495–502.

    Article  CAS  PubMed  Google Scholar 

  176. Li N, Oberley TD, Oberley LW, Zhong W. Overexpression of manganese superoxide dismutase in DU145 human prostate carcinoma cells has multiple effects on cell phenotype. Prostate. 1998;35:221–33.

    Article  CAS  PubMed  Google Scholar 

  177. Li S, Yan T, Yang J-Q, Oberley TD, Oberley LW. The role of cellular glutathione peroxidase redox regulation in the suppression of tumor cell growth by manganese superoxide dismutase. Cancer Res. 2000;60:3927–39.

    CAS  PubMed  Google Scholar 

  178. Li Y, Huang T-T, Carlson EJ, Melov S, Ursell PC, Olson JL, Noble LJ, Yoshimura MP, Berger C, Chan PH, Wallace DC, Epstein CJ. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet. 1995;11:376–81.

    Article  CAS  PubMed  Google Scholar 

  179. Li YY, Maisch B, Rose ML, Hengstenberg C. Point Mutations in Mitochondrial DNA of Patients with Dilated Cardiomyopathy. J Mol Cell Cardiol. 1997;29:2699–709.

    Article  CAS  PubMed  Google Scholar 

  180. Liu R, Oberley TD, Oberley LW. Transfection and expression of MnSOD cDNA decreases tumor malignancy of human oral sqamous carcinoma SCC-25 cells. Hum Gene Ther. 1997;8:585–95.

    Article  CAS  PubMed  Google Scholar 

  181. Longo VD, Liou L-L, Valentine JS, Gralla EB. Mitochondrial superoxide decreases yeast survival in stationary phase. Arch Biochem Biophys. 1999;365:131–42.

    Article  CAS  PubMed  Google Scholar 

  182. Lu J, Holmgren A. The thioredoxin antioxidant system. Free Radic Biol Med. 2014;66:75–87.

    Article  CAS  PubMed  Google Scholar 

  183. Lu J, Sharma LK, Bai Y. Implications of mitochondrial DNA mutations and mitochondrial dysfunction in tumorigenesis. Cell Res. 2009;19:802–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Lu S-P, Feng M-HL, Huang H-L, Huang Y-C, Tsou W-I, Lai M-Z. Reactive oxygen species promote raft formation in T lymphocytes. Free Radic Biol Med. 2007;42:936–44.

    Article  CAS  PubMed  Google Scholar 

  185. Lustgarten MS, Jang YC, Liu Y, Muller FL, Qi W, Steinhelper M, Brooks SV, Larkin L, Shimizu T, Shirasawa T, McManus LM, Bhattacharya A, Richardson A, Van Remmen H. Conditional knockout of Mn-SOD targeted to type IIB skeletal muscle fibers increases oxidative stress and is sufficient to alter aerobic exercise capacity. Am J Physiol Cell Physiol. 2009;297:C1520–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Lustgarten MS, Jang YC, Liu Y, Qi W, Qin Y, Dahia PL, Shi Y, Bhattacharya A, Muller FL, Shimizu T, Shirasawa T, Richardson A, Van Remmen H. MnSOD deficiency results in elevated oxidative stress and decreased mitochondrial function but does not lead to muscle atrophy during aging. Aging Cell. 2011;10:493–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. MacMillan-Crow LA, Cruthirds DL, Ahki KM, Sanders PW, Thompson JA. Mitochondrial tyrosine nitration precedes chronic allograft nephropathy. Free Radic Biol Med. 2001;31:1603–8.

    Article  CAS  PubMed  Google Scholar 

  188. MacMillan-Crow LA, Thompson JA. Tyrosine modifications and inactivation of active site manganese superoxide dismutase mutant (Y34F) by peroxynitrite. Arch Biochem Biophys. 1999;366:82–8.

    Article  CAS  PubMed  Google Scholar 

  189. Madsen-Bouterse SA, Zhong Q, Mohammad G, Ho Y-S, Kowluru RA. Oxidative damage of mitochondrial DNA in diabetes and its protection by manganese superoxide dismutase. Free Radic Res. 2010;44:313–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  190. Maiorino M, Scapin M, Ursini F, Biasolo M, Bosello V, Flohe L. Distinct promoters determine alternative transcription of gpx-4 into phospholipid-hydroperoxide glutathione peroxidase variants. J Biol Chem. 2003;278:34286–90.

    Article  CAS  PubMed  Google Scholar 

  191. Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol. 1995;146:3–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Malafa M, Margenthaler J, Webb B, Neitzel L, Christophersen M. MnSOD expression is increased in metastatic gastric cancer. J Surg Res. 2000;88:130–4.

    Article  CAS  PubMed  Google Scholar 

  193. Malecki EA, Greger JL. Manganese protects against heart mitochondrial lipid peroxidation in rats fed high levels of polyunsaturated fatty acids. J Nutr. 1996;126:27–33.

    CAS  PubMed  Google Scholar 

  194. Mambo E, Gao X, Cohen Y, Guo Z, Talalay P, Sidransky D. Electrophile and oxidant damage of mitochondrial DNA leading to rapid evolution of homplasmic mutations. Proc Natl Acad Sci. 2003;100:1838–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Mansouri A, Tarhuni A, Larosche I, Reyl-Desmars F, Demeilliers C, Degoul F, Nahon P, Sutton A, Moreau R, Fromenty B, Ressayre D. MnSOD overexpression prevents liver mitochondrial DNA depletion after an alcohol binge but worsens this effect after prolonged alcohol consumption in mice. Dig Dis. 2010;28:756–75.

    Article  PubMed  Google Scholar 

  196. Marecki JC, Parajuli N, Crow JP, MacMillan-Crow LA. The use of the Cre/loxP system to study oxidative stress in tissue-specific manganese superoxide dismutase knockout models. Antioxid Redox Signal. 2014;20:1655–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Martin FM, Xu X, von Lohneysen K, Gilmartin TJ, Friedman J. SOD2 deficient erythroid cells up-regulate transferrin receptor and down-regulate mitochondrial biogenesis and metabolism. PLoS One. 2011;6, e16894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Martinon F. Signaling by ROS drives inflammasome activation. Eur J Immunol. 2010;40:616–9.

    Article  CAS  PubMed  Google Scholar 

  199. Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol. 2009;27:229–65.

    Article  CAS  PubMed  Google Scholar 

  200. Mason RP. Using anti-5,5-dimethyl-1-pyrroline N-oxide (anti-DMPO) to detect protein radicals in time and space with immuno-spin trapping. Free Radic Biol Med. 2004;36:1214–23.

    Article  CAS  PubMed  Google Scholar 

  201. Mattson MP, Goodman Y, Luo H, Fu W, Furukawa K. Activation of NF-κΒ protects hippocampal neurons against oxidative stress-induced apoptosis: evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration. J Neurosci Res. 1997;49:681–97.

    Article  CAS  PubMed  Google Scholar 

  202. McLennan HR, Degli EM. The contribution fo mitochondrial respiratory complexes to the production of reactive oxygen species. J Bioenerg Biomembr. 2000;32:153–62.

    Article  CAS  PubMed  Google Scholar 

  203. McMillin JB, Dowhan W. Cardiolipin and apoptosis. Biochim Biophys Acta. 2002;1585:97–107.

    Article  CAS  PubMed  Google Scholar 

  204. Meissner F, Seger RA, Moshous S, Fischer A, Reichenbach J, Zychlinsky A. Inflammasome activation in NADPH oxidase defective mononuclear phagocytes from patients with chronic granulomatous disease. Blood. 2010;116:1570–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Miao L, St. Clair DK. Regulation of superoxide dismutase genes: implications in disease. Free Radic Biol Med. 2009;47(4):344–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004;56:185–229.

    Article  CAS  PubMed  Google Scholar 

  207. Miriyala S, Spasojevic I, Tovmasyan A, Salvemini D, Vujaskovic Z, St Clair D, Batinic-Haberle I. Manganese superoxide dismutase, MnSOD and its mimics. Biochim Biophys Acta. 2012;1822:794–814.

    Article  CAS  PubMed  Google Scholar 

  208. Misawa H, Nakata K, Matsuura J, Moriwaki Y, Kawashima K, Shimizu T, Shirawawa T, Takahashi R. Conditional knockout of Mn superoxide dismutase in postnatal motor neurons reveals resistance to mitochondrial generated superoxide radicals. Neurobiol Dis. 2006;23:169–77.

    Article  CAS  PubMed  Google Scholar 

  209. Misra HP, Fridovich I. Purification and properties of superoxide dismutase from a red alga, Porphyridium cruentum. J Biol Chem. 1977;252:6421–3.

    CAS  PubMed  Google Scholar 

  210. Miwa S, St.-Pierre J, Partridge L, Brand MD. Superoxide and hydrogen peroxide production by Drosophila mitochondria. Free Radic Biol Med. 2003;35:938–48.

    Article  CAS  PubMed  Google Scholar 

  211. Miyake A, Higashijima S-I, Kobayashi D, Narita T, Jindo T, Setiamarga DHE, Ohisa S, Orihara N, Hibiya K, Konno S, Sakaguchi S, Horie K, Imai Y, Naruse K, Kudo A, Takeda H. Mutation in the abcb7 gene causes abnormal iron and fatty acid metabolism in developing medaka fish. Develop Growth Differ. 2008;50:703–16.

    Article  CAS  Google Scholar 

  212. Mohr A, Buneker C, Gough RP, Zwacka RM. MnSOD protects colorectal cancer cells from TRAIL-induced apoptosis by inhibition of Smac/DIABLO release. Oncogene. 2008;27(6):763–74.

    Article  CAS  PubMed  Google Scholar 

  213. Monteiro-Cardoso VF, Oliveira MM, Melo T, Domingues MR, Moreira PI, Ferreiro E, Peixoto F, Videira RA. Cardiolipin profile changes are associated to the early synaptic mitochondrial dysfunction in Alzheimer’s disease. J Alzheimers Dis. 2015;43(4):1375–92.

    CAS  PubMed  Google Scholar 

  214. Monteiro JP, Oliveira PJ, Jurado AS. Mitochondrial membrane lipid remodeling in pathophysiology: a new target for diet and therapeutic interventions. Prog Lipid Res. 2013;52:513–28.

    Article  CAS  PubMed  Google Scholar 

  215. Morgan MJ, Lehmann M, Schwarzlander M, Baxter CJ, Sienkiewicz-Porzucek A, Williams TCR, Schauer N, Fernie AR, Fricker MD, Ratcliffe RG, Sweetlove LJ, Finkemeier I. Decrease in manganese superoxide dismutase leads to reduced root growth and affects tricarboxylic acid cycle flux and mitochondrial redox homeostasis. Plant Physiol. 2008;147:101–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Moulian N, Truffault F, Gaudry-Talarmain YM, Serraf A, Berrih-Aknin S. In vivo and in vitro apoptosis of human thymocytes are associated with nitrotyrosine formation. Blood. 2008;97:3521–30.

    Article  Google Scholar 

  217. Mukherjee S, Forde R, Belton A, Duttaroy A. SOD2, the principal scavenger of mitochondrial superoxide, is dispensable for embryogenesis and imaginal tissue development but essential for adult survival. Fly. 2011;5:39–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Muller FL, Liu Y, Van Remmen H. Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem. 2004;279:49064–73.

    Article  CAS  PubMed  Google Scholar 

  219. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417:1–13.

    Article  CAS  PubMed  Google Scholar 

  220. Murray J, Taylors SW, Zhang B, Ghosh SS, Capaldi RA. Oxidative damage to mitochondrial complex I due to peroxynitrite. Identification of reactive tyrosines by mass spectrometry. J Biol Chem. 2003;278:37223–30.

    Article  CAS  PubMed  Google Scholar 

  221. Nadtochiy SM, Baker PRS, Freeman BA, Brooks PS. Mitochondrial nitroalkene formation and mild uncoupling in ischaemic preconditioning: implications for cardioprotection. Cardiovasc Res. 2009;82:333–40.

    Article  CAS  PubMed  Google Scholar 

  222. Nahon P, Charnaux N, Friand V, Prost-Squarcioni C, Zoil M, Lievre N, Trinchet J-C, Beaugrand M, Gattegno L, Pessayre D, Sutton A. The manganese superoxide dismutase Ala16Val dimorphism modulates iron accumulation in human hepatoma cells. Free Radic Biol Med. 2008;45:1308–17.

    Article  CAS  PubMed  Google Scholar 

  223. Nakagawa Y. Initiation of apoptotic signal by the peroxidation of cardiolipin of mitochondria. Ann N Y Acad Sci. 2004;1011:177–84.

    Article  CAS  PubMed  Google Scholar 

  224. Nakahira K, Hapsel JA, Rathinam VAK, Lee S-J, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, Fitzgerald KA, Ryter SW, Choi AMK. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;8:222–30.

    Article  CAS  Google Scholar 

  225. Napier I, Ponka P, Richardson DR. Iron trafficking in the mitochondrion: novel pathways revealed by disease. Blood. 2005;105:1867–74.

    Article  CAS  PubMed  Google Scholar 

  226. Nelson CJ, Nandy N, Roth AJ. Chemotherapy and cognitive deficits: mechanisms, findings, and potential interventions. Palliat Support Care. 2007;5:273–80.

    Article  PubMed  Google Scholar 

  227. Nelson KK, Ranganathan AC, Mansouri J, Rodriguez AM, Providence KM, Rutter JL, Pumiglia K, Bennett JA, Melendez JA. Elevated Sod2 activity augments matrix metalloproteinase expression: evidence for the involvement of endogenous hydrogen peroxide in regulating metastasis. Clin Cancer Res. 2003;9:424–32.

    CAS  PubMed  Google Scholar 

  228. Nohl H, Jordan W. The metabolic fate of mitochondrial hydrogen peroxide. Eur J Biochem. 1980;111:203–10.

    Article  CAS  PubMed  Google Scholar 

  229. Nozoe T, Honda M, Inutsuka S, Yasuda M, Korenaga D. Significance of immunohistochemical expression of manganese superoxide dismutase as a marker of malignant potential in colorectal carcinoma. Oncol Rep. 2003;10:39–43.

    CAS  PubMed  Google Scholar 

  230. O’Donnell VB, Eiserich JP, Bloodsworth A, Chumley PH, Kirk M, Barnes S, Darley-Usmar VM, Freeman BA. Nitration of unsaturated fatty acids by nitric oxide-derived reactive species. Methods Enzymol. 1999;301:454–70.

    Article  PubMed  Google Scholar 

  231. Oberley LW. Mechanism of the tumor suppressive effect of MnSOD overexpression. Biomed Pharmacother. 2005;59:143–8.

    Article  CAS  PubMed  Google Scholar 

  232. Oberley LW, Buettner GR. Role of superoxide dismutase in cancer: a review. Cancer Res. 1979;39:1141–9.

    CAS  PubMed  Google Scholar 

  233. Oberley TD, Verwiebe E, Zhong W, Kang SW, Rhee SG. Localization of the thioredoxin system in normal rat kidney. Free Radic Biol Med. 2001;30:412–24.

    Article  CAS  PubMed  Google Scholar 

  234. Oh SS, Sullivan KA, Wilkinson JE, Backus C, Hayes JM, Sakowski SA, Feldman EL. Neurodegeneration and early lethality in superoxide dismutase 2-deficient mice: a comprehensive analysis of the central and peripheral nervous systems. Neuroscience. 2012;212:201–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Ohnishi T. Thermodynamic and EPR characterization of iron-sulfur centers in the NADH-ubiquinone segment of the mitochondrial respiratory chain in pigeon heart. Biochim Biophys Acta. 1975;387:475–90.

    Article  CAS  PubMed  Google Scholar 

  236. Ohnishi T. Iron-sulfur clusters/semiquinones in complex I. Biochim Biophys Acta. 1998;1364:186–206.

    Article  CAS  PubMed  Google Scholar 

  237. Ohnishi T, Tamai I, Sakanaka K, Sakata A, Yamashima T, Yamashita J, Tsuji A. In vivo and in vitro evidence for ATP-dependency of p-glycoprotein-mediated efflux of doxorubicin at the blood-brain barrier. Biochem Pharmacol. 1995;49:1541–4.

    Article  CAS  PubMed  Google Scholar 

  238. Ohtsuki T, Matsumoto M, Suzuki K, Taniguchi N, Kamada T. Mitochondrial lipid peroxidation and superoxide dismutase in rat hypertensive target organs. Am J Physiol Heart Circ Physiol. 1995;37:H1418–21.

    Google Scholar 

  239. Oida T, Suzuki K, Nanno M, Kanamori Y, Saito H, Kubota E, Kato S, Itoh M, Kaminogawa S, Ishikawa H. Role of gut cryptopatches in early extrathymic maturation of intestinal intraepithelial T cells. J Immunol. 2000;164:3616–26.

    Article  CAS  PubMed  Google Scholar 

  240. Okado-Matsumoto A, Fridovich I. Subcellular distribution of superoxide dismutases (SOD) in rat liver. Cu, Zn-SOD in mitochondria. J Biol Chem. 2001;276:38388–93.

    Article  CAS  PubMed  Google Scholar 

  241. Owusu-Ansah E, Banerjee U. Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature. 2009;461:537–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Padmaja S, Squadrito GL, Pryor WA. Inactivation of glutathione peroxidase by peroxynitrite. Arch Biochem Biophys. 1998;349:1–6.

    Article  CAS  PubMed  Google Scholar 

  243. Palazzotti B, Pani G, Colavitti R, de Leo ME, Bedogni B, Borrello S, Galeotti T. Increased growth capacity of cervical-carcinoma cells over-expressing manganous superoxide dismutase. Int J Cancer. 1999;82:145–50.

    Article  CAS  PubMed  Google Scholar 

  244. Panfili E, Sandri G, Ernster L. Distribution of glutathione peroxidases and glutathione reductase in rat brain mitochondria. FEBS Lett. 1991;290:35–7.

    Article  CAS  PubMed  Google Scholar 

  245. Pani G, Galeotti T, Chiarugi P. Metastasis: cancer cell’s escape from oxidative stress. Cancer Metastasis Rev. 2010;29:351–78.

    Article  CAS  PubMed  Google Scholar 

  246. Paradies G, Petrosillo G, Paradies V, Ruggiero FM. Role of cardiolipin peroxidation and Ca2+ in mitochondrial dysfunction and disease. Cell Calcium. 2009;45:643–50.

    Article  CAS  PubMed  Google Scholar 

  247. Paradies G, Petrosillo G, Paradies V, Ruggiero FM. Oxidative stress, mitochondrial bioenergetics, and cardiolipin in aging. Free Radic Biol Med. 2010;48:1286–95.

    Article  CAS  PubMed  Google Scholar 

  248. Paradies G, Petrosillo G, Pistolese M, Di Venosa N, Federici A, Ruggiero FM. Decrease in mitochondrial complex I activity in ischemic/reperfused rat heart. Involvement of reactive oxygen species and cardiolipin. Circ Res. 2004;94:53–9.

    Article  CAS  PubMed  Google Scholar 

  249. Paradies G, Petrosillo G, Pistolese M, Ruggiero FM. The effect of reactive oxygen species generated from the mitochondrial electron transport chain on the cytochrome c oxidase activity and on the cardiolipin content in bovine heart submitochondrial particles. FEBS Lett. 2000;466:323–6.

    Article  CAS  PubMed  Google Scholar 

  250. Paradies G, Petrosillo G, Pistolese M, Ruggiero FM. Reactive oxygen species generated by the mitochondrial respiratory chain affect the complex III activity via cardiolipin peroxidation in beef-heart submitochondrial particles. Mitochondrion. 2001;1:151–9.

    Article  CAS  PubMed  Google Scholar 

  251. Paradies G, Petrosillo G, Pistolese M, Ruggiero FM. Reactive oxygen species affect mitochondrial electron transport complex I activity through oxidative cardiolipin damage. Gene. 2002;286:135–41.

    Article  CAS  PubMed  Google Scholar 

  252. Parajuli N, Marine A, Simmons S, Saba H, Mitchell T, Shimizu T, Shirasawa T, MacMillan-Crow LA. Generation and characterization of a novel kidney-specific manganese superoxide dismutase knockout mouse. Free Radic Biol Med. 2011;51:406–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Pardo M, Melendez JA, Tirosh O. Manganese superoxide dismutase inactivation during Fas (CD95)-mediated apoptosis in Jurkat T cells. Free Radic Biol Med. 2006;41:1795–806.

    Article  CAS  PubMed  Google Scholar 

  254. Park SY, Chang I, Kim JY, Kang SW, Park SH, Singh K, Lee MS. Resistance of mitochondrial DNA-depleted cells against cell death: role of mitochondrial superoxide dismutase. J Biol Chem. 2004;279:7512–20.

    Article  CAS  PubMed  Google Scholar 

  255. Patel HH, McDonough AA. Of mice and men: modeling cardiovascular complexity in diabetes. Focus on “Mitochondrial inefficiencies and anoxic ATP hydrolysis capacities in diabetic rat heart”. Am J Physiol Cell Physiol. 2014;307:C497–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Paul A, Belton A, Nag S, Martin I, Grotewiel MS, Duttaroy A. Reduced mitochondrial SOD displays mortality characteristics reminiscent of natural aging. Mech Ageing Dev. 2007;128:706–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Paulsen CE, Carroll KS. Cysteine-mediated redox signaling: chemistry, biology, and tools for discovery. Chem Rev. 2013;113:4633–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Pearce LL, Epperly MW, Greenberger JS, Pitt BR, Peterson J. Identification of respiratory complexes I and III as mitochondrial sites of damage following exposure to ionizing radiation and nitric oxide. Nitric Oxide Biol Chem. 2001;5:128–36.

    Article  CAS  Google Scholar 

  259. Perez VI, Van Remmen H, Bokov A, Epstein CJ, Vijg J, Richardson A. The overexpression of major antioxidant enzymes does not extend the lifespan of mice. Aging Cell. 2009;8:73–5.

    Article  CAS  PubMed  Google Scholar 

  260. Petrosillo G, Casanova G, Matera M, Ruggiero FM, Paradies G. Interaction of peroxidized cardiolipin with rat-heart mitochondrial membranes: induction of permeability transition and cytochrome c release. FEBS Lett. 2006;580:6311–6.

    Article  CAS  PubMed  Google Scholar 

  261. Petrosillo G, Ruggiero FM, Pistolese M, Paradies G. Reactive oxygen species generated from the mitochondrial electron transport chain induce cytochrome c dissociation from beef-heart submitochondrial particles via cardiolipin peroxidation. Possible role in the apoptosis. FEBS Lett. 2001;509:435–8.

    Article  CAS  PubMed  Google Scholar 

  262. Pfeiffer K, Gohil V, Stuart RA, Hunte C, Brandt U, Greenberg ML, Schagger H. Cardiolipin stabilizes respiratory chain supercomplexes. J Biol Chem. 2003;278:52873–80.

    Article  CAS  PubMed  Google Scholar 

  263. Picone P, Nuzzo D, Caruana L, Scafidi V, Di Carlo M. Mitochondrial dysfunction: different routes to Alzheimer’s disease therapy. Oxid Med Cell Longev. 2014;2014:780179.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  264. Piganelli JD, Flores SC, Cruz C, Koepp J, Batinic-Haberle I, Crapo J, Day B, Kachadourian R, Young R, Bradley B, Haskins K. A metalloporphyrin-based superoxide dismutase mimic inhibits adoptive transfer of autoimmune diabetes by a diabetogenic T-cell clone. Diabetes. 2002;51:347–55.

    Article  CAS  PubMed  Google Scholar 

  265. Pinkham JL, Wang Z, Alsina J. Heme regulates SOD2 transcription by activation and repression in Saccharomyces cerevisiae. Curr Genet. 1997;31:281–91.

    Article  CAS  PubMed  Google Scholar 

  266. Poli G, Leonarduzzi G, Biasi F, Chiarpotto E. Oxidative stress and cell signaling. Curr Med Chem. 2004;11:1163–82.

    Article  CAS  PubMed  Google Scholar 

  267. Pondarre C, Antiochos BB, Campagna DR, Clarke SL, Greer EL, Deck KM, McDonald A, Han A-P, Medlock A, Kutok JL, Anderson SA, Einsenstein RS, Fleming MD. The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron-sulfur cluster biogenesis. Hum Mol Genet. 2006;15:953–64.

    Article  CAS  PubMed  Google Scholar 

  268. Powell CS, Jackson RM. Mitochondrial complex I, aconitase, and succinate dehydrogenase during hypoxia-reoxygenation: modulation of enzyme activities by MnSOD. Am J Physiol Lung Cell Mol Physiol. 2003;285:L189–98.

    Article  CAS  PubMed  Google Scholar 

  269. Powis G, Kirkpatrick DL. Thioredoxin signaling as a target for cancer therapy. Curr Opin Pharmacol. 2007;7:392–7.

    Article  CAS  PubMed  Google Scholar 

  270. Quiros-Gonzalez I, Sainz RM, Hevia D, Mayo JC. MnSOD drives neuroendocrine differentiation, androgen independence, and cell survival in prostate cancer cells. Free Radic Biol Med. 2011;50:525–36.

    Article  CAS  PubMed  Google Scholar 

  271. Quiros I, Sainz RM, Hevia D, Garcia-Suarez O, Astudillo A, Rivas M, Mayo JC. Upregulation of manganese superoxide dismutase (SOD2) is a common pathway for neuroendocrine differentiation in prostate cancer cells. Int J Cancer. 2009;125(7):1497–504.

    Article  CAS  PubMed  Google Scholar 

  272. Radi R, Beckman JS, Bush KM, Freeman BA. Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide. Arch Biochem Biophys. 1991;288:481–7.

    Article  CAS  PubMed  Google Scholar 

  273. Radi R, Beckman JS, Bush KM, Freeman BA. Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. J Biol Chem. 1991;266:4244–50.

    CAS  PubMed  Google Scholar 

  274. Radi R, Cassina A, Hodara R, Quijano C, Castro L. Peroxynitrite reactions and formation in mitochondria. Free Radic Biol Med. 2002;33:1451–64.

    Article  CAS  PubMed  Google Scholar 

  275. Radi R, Rodriquez M, Castro L, Telleri R. Inhibition of mitochondrial electron transport by peroxynitrite. Arch Biochem Biophys. 1994;308:89–95.

    Article  CAS  PubMed  Google Scholar 

  276. Radi R, Turrens JF, Chang LY, Bush KM, Crapo JD, Freeman BA. Detection of catalase in rat heart mitochondria. J Biol Chem. 1991;266:22028–34.

    CAS  PubMed  Google Scholar 

  277. Raha S, Robinson BH. Mitochondria, oxygen free radicals, disease, and ageing. Trends Biochem Sci. 2000;25:502–8.

    Article  CAS  PubMed  Google Scholar 

  278. Raha S, Robinson BH. Mitochondria, oxygen free radicals, and apoptosis. Am J Med Genet. 2001;106:62–70.

    Article  CAS  PubMed  Google Scholar 

  279. Ranganathan AC, Nelson KK, Rodriguez AM, Kim K-H, Tower GB, Rutter JL, Brinckerhoff CE, Huang T-T, Epstein CJ, Jeffrey JJ, Melendez JA. Manganese superoxide dismutase signals matrix metalloproteinase expression via H2O2-dependent ERK1/2 activation. J Biol Chem. 2001;276:14264–70.

    CAS  PubMed  Google Scholar 

  280. Ravindranath SD, Fridovich I. Isolation and characterization of a manganese-containing superoxide dismutase from yeast. J Biol Chem. 1975;250:6107–12.

    CAS  PubMed  Google Scholar 

  281. Reed JC. Mechanisms of apoptosis. Am J Pathol. 2000;157:1415–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Reynier M, Sari H, d’Anglebermes M, Kye EA, Pasero L. Differences in lipid characteristics of undifferentiated and enterocytic-differentiated HT29 human colonic cells. Cancer Res. 1991;51:1270–7.

    CAS  PubMed  Google Scholar 

  283. Rhee SG, Chang T-S, Bae YS, Lee S-R, Kang SW. Cellular regulation by hydrogen peroxide. J Am Soc Nephrol. 2003;14:S211–5.

    Article  CAS  PubMed  Google Scholar 

  284. Richardson DR, Lane DJR, Becker EM, Huang ML-H, Witnall M, Rahmanto YS, Sheftel AD, Ponka P. Mitochondrial iron trafficking and the integration of metabolism between the mitochondrion and cytosol. Proc Natl Acad Sci. 2010;107:10775–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Richter C, Park J-W, Ames BN. Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci U S A. 1988;85:6465–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Ridnour LA, Oberley TD, Oberley LW. Tumor suppressive effects of MnSOD overexpression may involve imbalance in peroxide generation versus peroxide removal. Antioxid Redox Signal. 2004;6:501–12.

    Article  CAS  PubMed  Google Scholar 

  287. Riobo NA, Clementi E, Melani M, Boveris A, Cadenas E, Moncada S, Poderoso JJ. Nitric oxide inhibits mitochondrial NADH:ubiquinone reductase activity through peroxynitrite formation. Biochem J. 2001;359:139–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Roessler MM, King MS, Robinson AJ, Armstrong FA, Harmer J, Hirst J. Direct assignment of EPR spectra to structurally defined iron-sulfur clusters in complex i by double electron-electron resonance. Proc Natl Acad Sci U S A. 2010;107:1930–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Rotig A, de Lonlay P, Chretien D, Foury F, Koenig M, Sidi D, Munnich A, Rustin P. Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat Genet. 1997;17:215–7.

    Article  CAS  PubMed  Google Scholar 

  290. Rouault TA, Tong W-H. iron-sulphur cluster biogenesis and mitochondrial iron homeostasis. Nat Rev Mol Cell Biol. 2005;6:345–51.

    Article  CAS  PubMed  Google Scholar 

  291. Roy S, Nicholson DW. Cross-talk in cell death signaling. J Exp Med. 2000;192:F21–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  292. Rubbo H, Trostchansky A, O’Donnell VB. Peroxynitrite-mediated lipid oxidation and nitration: mechanisms and consequences. Arch Biochem Biophys. 2009;484:167–72.

    Article  CAS  PubMed  Google Scholar 

  293. Salvi M, Battaglia V, Brunati AM, La Rocca N, Tibaldi E, Pietrangeli P, Marcocci L, Mondovi B, Rossi CA, Toninello A. Catalase takes part in rat liver mitochondria oxidative stress defense. J Biol Chem. 2007;282:24407–15.

    Article  CAS  PubMed  Google Scholar 

  294. Salzman R, Kankova K, Pacal L, Tomandl J, Horakova Z, Kostrica R. Increased activity of superoxide dismutase in advanced stages of head and neck squamous cell carcinoma with locoregional metastases. Neoplasma. 2007;54:321–5.

    CAS  PubMed  Google Scholar 

  295. Sarvazyan N. Visualization of doxorubicin-induced oxidative stress in isolated cardiac myocytes. Am J Physiol Heart Circ Physiol. 1996;271:H2079–85.

    CAS  Google Scholar 

  296. Sato K, Torimoto Y, Hosoki T, Ikuta K, Takahashi H, Yamamoto M, Ito S, Okamura N, Ichiki K, Tanaka H, Shindo M, Hirai K, Mizukami Y, Otake T, Fujiya M, Sasaki K, Kohgo Y. Loss of ABCB7 gene: pathogenesis of mitochondrial iron accumulation in erythroblasts in refractory anemia with ringed siderblast with isodicentric (X)(q13). Int J Hematol. 2011;93:311–8.

    Article  PubMed  Google Scholar 

  297. Schafer M, Schafer C, Ewald N, Piper HM, Noll T. Role of redox signaling in the autonomous proliferative response of endothelial cells to hypoxia. Circ Res. 2003;92:1010–5.

    Article  CAS  PubMed  Google Scholar 

  298. Schug ZT, Gottlieb E. Cardiolipin acts as a mitochondrial signalling platform to launch apoptosis. Biochim Biophys Acta. 2009;1788:2022–31.

    Article  CAS  PubMed  Google Scholar 

  299. Schwartzman RA, Cidlowski JA. Apoptosis: the biochemistry and molecular biology of programmed cell death. Endocr Rev. 1993;14:133–51.

    CAS  PubMed  Google Scholar 

  300. Seo MS, Kang SW, Kim K, Baines IC, Lee TH, Rhee SG. Identification of a new type of mammalian peroxiredoxin that forms an intramolecular disulfide as a reaction intermediate. J Biol Chem. 2000;275:20346–54.

    Article  CAS  PubMed  Google Scholar 

  301. Seth RB, Sun L, Ea C-K, Chen ZJ. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF3. Cell. 2005;122:669–82.

    Article  CAS  PubMed  Google Scholar 

  302. Sharoyko VV, Abels M, Sun J, Nicholas LM, Mollet IG, Stamenkovic JA, Gohring I, Malmgren S, Storm P, Fadista J, Spegel P, Metodiev MD, Larsson NG, Eliasson L, Wierup N, Mulder H. Loss of TFB1M results in mitochondrial dysfunction that leads to impaired insulin secretion and diabetes. Hum Mol Genet. 2014;23(21):5733–49.

    Article  CAS  PubMed  Google Scholar 

  303. Shen X, Zheng S, Metreveli NS, Epstein PN. Protection of cardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy. Diabetes. 2006;55:798–805.

    Article  CAS  PubMed  Google Scholar 

  304. Shibata E, Nanri H, Ejima K, Araki M, Fukuda J, Yoshimura K, Toki N, Ikeda M, Kashimura M. Enhancement of mitochondrial oxidative stress and up-regulation of antioxidant protein peroxiredoxin III/SP-22 in the mitochondria of human pre-eclamptic placentae. Placenta. 2003;24:698–705.

    Article  CAS  PubMed  Google Scholar 

  305. Shimada Y, Okuno S, Kawai A, Shinomiya H, Saito A, Suzuki M, Omori Y, Nishino N, Kanemoto N, Fujiwara T, Horie M, Takahashi E-I. Cloning and chromosomal mapping of a novel ABC transporter gene (hABC7), a candidate for X-linked sideroblastic anemia with spinocerebellar ataxia. J Hum Genet. 1998;43:115–22.

    Article  CAS  PubMed  Google Scholar 

  306. Shioji K, Kishimoto C, Nakamura H, Masutani H, Yuan Z, Oka S-I, Yodoi J. Overexpression of thioredoxin-1 in transgenic mice attenuates adriamycin-induced cardiotoxicity. Circulation. 2002;106:1403–9.

    Article  CAS  PubMed  Google Scholar 

  307. Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, Nair KS. Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci. 2005;102:5618–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  308. Sidiropoulos PI, Goulielmos G, Voloudakis GK, Petraki E, Boumpas DT. Inflammasomes and rheumatic diseases: evolving concepts. Ann Rheum Dis. 2008;67:1382–9.

    Article  CAS  PubMed  Google Scholar 

  309. Silverman DHS, Dy CJ, Castellon SA, Lai J, Pio BS, Abraham L, Waddell K, Petersen L, Phelps ME, Ganz PA. Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy. Breast Cancer Res Treat. 2007;103:303–11.

    Article  CAS  PubMed  Google Scholar 

  310. Simbre II VC, Duffy SA, Dadlani GH, Miller TL, Lipshultz SE. Cardiotoxicity of cancer chemotherapy. Implications for children. Pediatr Drugs. 2005;7:187–202.

    Article  Google Scholar 

  311. Siuda J, Jasinska-Myga B, Boczarska-Jedynak M, Opala G, Fiesel FC, Moussaud-Lamodiere EL, Scarffe LA, Dawson VL, Ross OA, Springer W, Dawson TM, Wszolek ZK. Early-onset Parkinson’s disease due to PINK1 p.Q456X mutation—clinical and functional study. Parkinsonism Relat Disord. 2014;20(11):1274–8.

    Article  PubMed  PubMed Central  Google Scholar 

  312. Slot JW, Geuze HJ, Freeman BA, Crapo JD. Intracellular localization of the copper-zinc and manganese superoxide dismutases in rat liver parenchymal cells. Lab Investig. 1986;55:363–71.

    CAS  PubMed  Google Scholar 

  313. Soini Y, Vakkala M, Kahlos K, Paakko P, Kinnla V. MnSOD expression is less frequent in tumour cells of invasive breast carcinomas than in in situ carcinomas or non-neoplastic breast epithelial cells. J Pathol. 2001;195:156–62.

    Article  CAS  PubMed  Google Scholar 

  314. Sorice M, Manganelli V, Matarrese P, Tinari A, Misasi R, Malorni W, Garofalo T. Cardiolipin-enriched raft-like microdomains are essential activating platforms for apoptotic signals on mitochondria. FEBS Lett. 2009;583:2447–50.

    Article  CAS  PubMed  Google Scholar 

  315. Sparagna GC, Johnson CA, McCune SA, Moore RL, Murphy RC. Quantitation of cardiolipin molecular species in spontaneously hypertensive heart failure rats using electrospray ionization mass spectrometry. J Lipid Res. 2005;46:1196–204.

    Article  CAS  PubMed  Google Scholar 

  316. Spickett CM, Wiswedel I, Siems W, Zarkovic K, Zarkovic N. Advances in methods for the determination of biologically relevant lipid peroxidation products. Free Radic Res. 2010;44:1172–202.

    Article  CAS  PubMed  Google Scholar 

  317. Spierings D, McStay G, Saleh M, Bender C, Chipuk J, Maurer U, Green DR. Connected to death: the (unexpurgated) mitochondrial pathway of apoptosis. Science. 2005;310:66–7.

    Article  CAS  PubMed  Google Scholar 

  318. Spyrou G, Enmark E, Miranda-Vizuete A, Gustafsson J-Å. Cloning and expression of a novel mammalian thioredoxin. J Biol Chem. 1997;272:2936–41.

    Article  CAS  PubMed  Google Scholar 

  319. Squadrito GL, Pryor WA. The formation of peroxynitrite in vivo from nitric oxide and superoxide. Chem Biol Interact. 1995;96:203–6.

    Article  CAS  PubMed  Google Scholar 

  320. Srinivasan C, Liba A, Imlay JA, Valentine JS, Gralla EB. Yeast lacking superoxide dismutase(s) show elevated levels of “free iron” as measured by whole cell electron paramagnetic resonance. J Biol Chem. 2000;275:29187–92.

    Article  CAS  PubMed  Google Scholar 

  321. St Clair DK, Oberley TD, Ho YS. Overproduction of human Mn-superoxide dismutase modulates paraquat-mediated toxicity in mammalian cells. FEBS Lett. 1991;293:199–203.

    Article  CAS  PubMed  Google Scholar 

  322. St. Clair DK, Wang XS, Oberley TD, Muse KE, St. Clair WH. Suppression of radiation-induced neoplastic transformation by overexpression of mitochondrial superoxide dismutase. Mol Carcinog. 1992;6:238–42.

    Article  CAS  PubMed  Google Scholar 

  323. Starkov AA, Fiskum G, Chinopoulos C, Lorenzo BJ, Browne SE, Patel MS, Beal MF. Mitochondrial α-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci. 2004;24:7779–88.

    Article  CAS  PubMed  Google Scholar 

  324. Steinman HM, Weinstein L, Brenowitz M. The manganese superoxide dismutase of Escherichia coli K-12 associates with DNA. J Biol Chem. 1994;269:28629–34.

    CAS  PubMed  Google Scholar 

  325. Strassburger M, Bloch W, Sulyok S, Schuller J, Keist AF, Schmidt A, Wenk J, Peters T, Wlaschek M, Krieg T, Hafner M, Kumin A, Werner S, Muller W, Scharffetter-Kochanek K. Heterozygous deficiency of manganese superoxide dismutase results in severe lipid peroxidation and spontaneous apoptosis in murine myocardium in vivo. Free Radic Biol Med. 2005;38:1458–70.

    Article  CAS  PubMed  Google Scholar 

  326. Sun J, Folk D, Bradley TJ, Tower J. Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster. Genetics. 2002;161:661–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  327. Sun X, Zhou Z, Kang YJ. Attenuation of doxorubicin chronic toxicity in metallothionein-overexpressing transgenic mouse heart. Cancer Res. 2001;61:3382–7.

    CAS  PubMed  Google Scholar 

  328. Sun XZ, Vinci C, Makmura L, Han S, Tran D, Nguyen J, Hamann M, Grazziani S, Sheppard S, Gutova M, Zhou F, Thomas J, Momand J. Formation of disulfide bond in p53 correlates with inhibition of DNA binding and tetramerization. Antioxid Redox Signal. 2003;5:655–65.

    Article  CAS  PubMed  Google Scholar 

  329. Takai D, Park S-H, Takada Y, Ichinose S, Kitagawa M, Akashi M. UV-irradiation induces oxidative damage to mitochondrial DNA primarily through hydrogen peroxide: analysis of 8-oxodGuo by HPLC. Free Radic Res. 2006;40:1138–48.

    Article  CAS  PubMed  Google Scholar 

  330. Takeshige K, Minakami S. NADH- and NADPH-dependent formation of superoxide anions by bovine heart submitochondrial particles and NADH-ubiquinone reductase preparation. Biochem J. 1979;180:129–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  331. Tan AS, Baty JW, Berridge MV. The role of mitochondrial electron transport in tumorigenesis and metastasis. Biochim Biophys Acta. 2014;1840:1454–63.

    Article  CAS  PubMed  Google Scholar 

  332. Tanaka M, Kovalenko SA, Gong J-S, Borgeld H-JW, Katsumata K, Hayakawa M, Yoneda M, Ozawa T. Accumulation of deletions and point mutations in mitochondrial genome in degenerative diseases. Ann N Y Acad Sci. 1996;786:102–11.

    Article  CAS  PubMed  Google Scholar 

  333. Tangpong J, Cole MP, Sultana R, Estus S, Vore M, St. Clair W, Ratanachaiyavong S, St. Clair DK, Butterfield DA. Adriamycin-mediated nitration of manganese superoxide dismutase in the central nervous system: insight into the mechanism of chemobrain. J Neurochem. 2007;100:191–201.

    Article  CAS  PubMed  Google Scholar 

  334. Tangpong J, Cole MP, Sultana R, Joshi G, Estus S, Vore M, St. Clair W, Ratanachaiyavong S, St. Clair DK, Butterfield DA. Adriamycin-induced, TNF-α-mediated central nervous system toxicity. Neurobiol Dis. 2006;23:127–39.

    Article  CAS  PubMed  Google Scholar 

  335. Tangpong J, Sompol P, Vore M, St Clair W, Butterfield DA, St Clair DK. Tumor necrosis factor alpha-mediated nitric oxide production enhances manganese superoxide dismutase nitration and mitochondrial dysfunction in primary neurons: an insight into the role of glial cells. Neuroscience. 2008;151:622–9.

    Article  CAS  PubMed  Google Scholar 

  336. Tannock IF, Ahles TA, Ganz PA, van Dam FS. Cognitive impairment associated with chemotherapy for cancer: report of a workshop. J Clin Oncol. 2004;22:2233–9.

    Article  PubMed  Google Scholar 

  337. Teintze M, Slaughter M, Weiss H, Neupert W. Biogenesis of mitochondrial ubiquinol:cytochrome c reductase (cytochrome bc 1 complex). Precursor proteins and their transfer into mitochondria. J Biol Chem. 1982;257:10364–71.

    CAS  PubMed  Google Scholar 

  338. Tortora V, Quijano C, Freeman B, Radi R, Castro L. Mitochondrial aconitase reaction with nitric oxide, S-nitrosoglutathione, and peroxynitrite: mechanisms and relative contributions to aconitase inactivation. Free Radic Biol Med. 2007;42:1075–88.

    Article  CAS  PubMed  Google Scholar 

  339. Tretter L, Adam-Vizi V. Generation of reactive oxygen species in the reaction catalyzed by α-ketoglutarate dehydrogenase. J Neurosci. 2004;24:7771–8.

    Article  CAS  PubMed  Google Scholar 

  340. Trumpower BL. The protonmotive Q cycle. Energy transduction by coupling of proton translocation to electron transfer by the cytochrome bc 1 complex. J Biol Chem. 1990;265:11409–12.

    CAS  PubMed  Google Scholar 

  341. Tsanou E, Ioachim E, Briasoulis E, Damala K, Charchanti A, Karavasilis V, Pavlidis N, Agnantis NJ. Immunohistochemical expression of superoxide dismutase (MnSOD) anti-oxidant enzyme in invasive breast carcinoma. Histol Histopathol. 2004;19:807–13.

    CAS  PubMed  Google Scholar 

  342. Tyurina YY, Tyurin VA, Kaynar AM, Kapralova VI, Wasserloos K, Li J, Mosher M, Wright L, Wipf P, Watkins S, Pitt BR, Kagan VE. Oxidative lipidomics of hyperoxic acute lung injury: mass spectrometric characterization of cardiolipin and phosphatidylserine. Am J Physiol Lung Cell Mol Physiol. 2010;299:L73–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  343. van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson NL, Baynes JW, Epstein CJ, Huang T-T, Nelson J, Strong R, Richardson A. Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics. 2003;16:29–37.

    Article  PubMed  CAS  Google Scholar 

  344. Vashchenko N, Abrahamsson PA. Neuroendocrine differentiation in prostate cancer: implications for new treatment modalities. Eur Urol. 2005;47:147–55.

    Article  CAS  PubMed  Google Scholar 

  345. Venkataraman S, Jiang X, Weydert C, Zhang Y, Zhang HJ, Goswami PC, Ritchie JM, Oberley LW, Buettner GR. Manganese superoxide dismutase overexpression inhibits the growth of androgen-independent prostate cancer cells. Oncogene. 2005;24:77–89.

    Article  CAS  PubMed  Google Scholar 

  346. Walker V. Ammonia toxicity and its prevention in inherited defects of the urea cycle. Diabetes Obes Metab. 2009;11:823–35.

    Article  CAS  PubMed  Google Scholar 

  347. Wang X, Martindale JL, Liu Y, Holbrook NJ. The cellular response to oxidative stress: influences of mitogen-activated protein kinase signaling pathways on cell survival. BioChem J. 1998;333:291–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  348. Wang X, Peralta S, Moraes CT. Chapter four—mitochondrial alterations during carcinogenesis: a review of metabolic transformation and targets for anticancer treatments. In: Kenneth DT, Paul BF, editors. Advances in Cancer Research. Orlando: Academic; 2013. p. 127–60.

    Google Scholar 

  349. Waris G, Ahsan H. Reactive oxygen species: role in the development of cancer and various chronic conditions. J Carcinog. 2006;5:14–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  350. Wefel JS, Lenzi R, Theriault R, Buzdar AU, Cruickshank S, Meyers CA. ‘Chemobrain’ in breast carcinoma? A prologue. Cancer. 2004;101:466–75.

    Article  PubMed  Google Scholar 

  351. Weisiger RA, Fridovich I. Mitochondrial superoxide dismutase. Site of synthesis and intramitochondrial localization. J Biol Chem. 1973;248:4793–6.

    CAS  PubMed  Google Scholar 

  352. Weydert C, Roling B, Liu J, Hinkhouse MM, Ritchie JM, Oberley LW, Cullen JJ. Suppression of the malignant phenotype in human pancreatic cancer cells by the overexpression of manganese superoxide dismutase. Mol Cancer Ther. 2003;2:361–9.

    CAS  PubMed  Google Scholar 

  353. Williams D, Venardos KM, Byrne M, Joshi M, Horlock D, Lam NT, Gregorevic P, McGee SL, Kaye DM. Abnormal mitochondrial L-arginine transport contributes to the pathogenesis of heart failure and rexoygenation injury. PLoS One. 2014;9:e104643.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  354. Williams MD, Van Remmen H, Conrad CC, Huang T-T, Epstein CJ, Richardson A. Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice. J Biol Chem. 1998;273:28510–5.

    Article  CAS  PubMed  Google Scholar 

  355. Wiswedel I, Gardemann A, Storch A, Peter D, Schild L. Degradation of phospholipids by oxidative stress—exceptional significance of cardiolipin. Free Radic Res. 2010;44:135–45.

    Article  CAS  PubMed  Google Scholar 

  356. Wiswedel I, Keilhoff G, Dorner L, Navarro A, Bockelmann R, Bonnekoh B, Gardemann A, Gollnick H. UVB irradiation-induced impairment of keratinocytes and adaptive responses to oxidative stress. Free Radic Res. 2007;41:1017–27.

    Article  CAS  PubMed  Google Scholar 

  357. Wittig I, Schagger H. Supramolecular organization of ATP synthase and respiratory chain in mitochondrial membranes. Biochim Biophys Acta. 2009;1787:672–80.

    Article  CAS  PubMed  Google Scholar 

  358. Wong GHW, Elwell JH, Oberley LW, Goeddel DV. Manganese superoxide dismutase is essential for cellular resistance to cytotoxicity of tumor necrosis factor. Cell. 1989;58:923–31.

    Article  CAS  PubMed  Google Scholar 

  359. Wong GHW, Goeddel DV. Induction of manganous superoxide dismutase by tumor necrosis factor: possible protective role. Science. 1988;242:941–4.

    Article  CAS  PubMed  Google Scholar 

  360. Wright VP, Reiser PJ, Clanton TL. Redox modulation of global phosphatase activity and protein phosphorylation in intact skeletal muscle. J Physiol. 2009;587:5767–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  361. Xu Y, Porntadavity S, St. Clair DK. Transcriptional regulation of the human manganese superoxide dismutase gene: the role of specificity protein 1 (Sp1) and activating protein-2 (AP-2). Biochem J. 2002;362:401–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  362. Yakes FM, van Houten B. Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci U S A. 1997;94:514–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  363. Yamamoto T, Maruyama W, Kato Y, Yi H, Shamoto-Nagai M, Tanaka M, Sato Y, Naoi M. Selective nitration of mitochondrial complex I by peroxynitrite: involvement of mitochondria dysfunction and cell death of dopaminergic SH-SY5Y cells. J Neural Transm. 2002;109:1–13.

    Article  CAS  PubMed  Google Scholar 

  364. Yang L-Y, Chen W-L, Lin J-W, Lee S-F, Lee C-C, Hung TI, Wei Y-H, Shih C-M. Differential expression of antioxidant enzymes in various hepatocellular carcinoma cell lines. J Cell Biochem. 2005;96:622–31.

    Article  CAS  PubMed  Google Scholar 

  365. Yang Y, Karakhanova S, Werner J, Bazhin AV. Reactive oxygen species in cancer biology and anticancer therapy. Curr Med Chem. 2013;20:3677–92.

    Article  CAS  PubMed  Google Scholar 

  366. Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD. Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2009;106:14670–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  367. Ye H, Rouault TA. Human iron-sulfur cluster assembly, cellular iron homeostasis, and disease. Biochemistry. 2010;49:4945–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  368. Yen H-C, Oberley TD, Gairola CG, Szweda LI, St. Clair DK. Manganese superoxide dismutase protects mitochondrial complex I against adriamycin-induced cardiomyopathy in transgenic mice. Arch Biochem Biophys. 1999;362:59–66.

    Article  CAS  PubMed  Google Scholar 

  369. Yen H-C, Oberley TD, Vichitbandha S, Ho Y-S, St. Clair DK. The protective role of manganese superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice. J Clin Investig. 1996;98:1253–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  370. Zamocky M, Furtmuller PG, Obinger C. Evolution of catalases from bacteria to humans. Antioxid Redox Signal. 2008;10:1527–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  371. Zelko IN, Mariani TJ, Felz RJ. Superoxide dismutase multigene family: a comparison of CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structure, evolution, and expression. Free Radic Biol Med. 2002;33:337–49.

    Article  CAS  PubMed  Google Scholar 

  372. Zhang L, Yu L, Yu C-A. Generation of superoxide anion by succinate-cytochrome c reductase from bovine heart mitochondria. J Biol Chem. 1998;273:33972–6.

    Article  CAS  PubMed  Google Scholar 

  373. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  374. Zhang Y, Smith BJ, Oberley LW. Enzymatic activity is necessary for the tumor-suppressive effects of MnSOD. Antioxid Redox Signal. 2006;8:1283–93.

    Article  CAS  PubMed  Google Scholar 

  375. Zhao Y, Chaiswing L, Oberley TD, Batinic-Haberle I, St. Clair W, Epstein CJ, St. Clair DK. A mechanism-based antioxidant approach for the reduction of skin carcinogenesis. Cancer Res. 2005;65:1401–5.

    Article  CAS  PubMed  Google Scholar 

  376. Zhao Y, Kiningham KK, Lin S-M, St. Clair DK. Overexpression of MnSOD protects murine fibrosarcoma cells (FSa-II) from apoptosis and promotes a differentiation program upon treatment with 5-azacytidine: involvement of MAPK and NFκB pathways. Antioxid Redox Signal. 2001;3:375–86.

    Article  CAS  PubMed  Google Scholar 

  377. Zhao Y, Oberley TD, Chaiswing L, Lin S-M, Epstein CJ, Huang T-T, St. Clair DK. Manganese superoxide dismutase deficiency enhances cell turnover via tumor promoter-induced alterations in AP-1 and p53-mediated pathways in a skin cancer model. Oncogene. 2002;21:3836–46.

    Article  CAS  PubMed  Google Scholar 

  378. Zhao Y, Xue Y, Oberley TD, Kiningham KK, Lin S-M, Yen H-C, Majima H, Hines J, St. Clair DK. Overexpression of manganese superoxide dismutase suppresses tumor formation by modulation of activator protein-1 signaling in a multistage skin carcinogenesis model. Cancer Res. 2001;61:6082–8.

    CAS  PubMed  Google Scholar 

  379. Zhou Z, Kang YJ. Cellular and subcellular localization of catalase in the heart of transgenic mice. J Histochem Cytochem. 2000;48:585–94.

    Article  CAS  PubMed  Google Scholar 

  380. Zidenberg-Cherr S, Keen CL, Lonnerdal B, Hurley LS. Superoxide dismutase activity and lipid peroxidation in the rat: developmental correlations affected by manganese deficiency. J Nutr. 1983;113:2498–504.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine/Division of Gastroenterology, University of Kentucky, 800 Rose St., Lexington, KY, 40536, USA

    Aaron K. Holley

  2. Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY, 40536, USA

    Daret K. St. Clair

Authors
  1. Aaron K. Holley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daret K. St. Clair
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Aaron K. Holley or Daret K. St. Clair .

Editor information

Editors and Affiliations

  1. Duke University School of Medicine, Durham, North Carolina, USA

    Ines Batinić-Haberle

  2. Universidade Federal da Paraíba, João Pessoa, Paraíba, Brazil

    Júlio S. Rebouças

  3. Duke University School of Medicine, Durham, North Carolina, USA

    Ivan Spasojević

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Holley, A.K., St. Clair, D.K. (2016). Manganese Superoxide Dismutase (MnSOD) and Its Importance in Mitochondrial Function and Cancer. In: Batinić-Haberle, I., Rebouças, J., Spasojević, I. (eds) Redox-Active Therapeutics. Oxidative Stress in Applied Basic Research and Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-30705-3_3

Download citation

Publish with us

Policies and ethics

Search

Navigation