Advertisement

Role of Mitochondrial Reactive Oxygen and Nitrogen Species in Respiratory Diseases

  • Harijith Anantha
  • Prasad Kanteti
  • Panfeng Fu
  • Sainath R. Kotha
  • Narasimham L. Parinandi
  • Viswanathan NatarajanEmail author
Chapter
Part of the Respiratory Medicine book series (RM, volume 15)

Abstract

Mitochondria are key cellular organelles that not only supply cellular ATP but also integrate redox signaling, apoptotic balance, and biosynthetic pathways in the cell. Mitochondrial dysfunction leads to loss of cellular function, and in humans, mitochondrial dysfunction causes numerous pathologies including cancer, cardiovascular disease, neurological disorders, and respiratory diseases. Mitochondria are a major source of cellular reactive oxygen species (ROS), and mitochondrial ROS production is tightly regulated by the various states of electron transport chain and antioxidant systems present within the mitochondria. As accumulation of mitochondria-derived ROS have been linked to several human diseases, a better understanding of mitochondrial ROS signaling and regulation of its production and function is clinically relevant under physiological and pathological situations. Further, as mitochondrial ROS is linked to mitochondrial dysfunction in various human pathologies, targeting mitochondrial ROS with specific antioxidants has been an area of intense investigation. Thus, there is considerable evidence for mitochondrial ROS in normal cell function and signaling, and in this review, we discuss recent advances on the generation, regulation, and targeting of mitochondrial ROS.

Keywords

Mitochondria Oxidative stress ROS RNS Respiratory diseases 

References

  1. 1.
    Verschoor, et al. BioMed Res Int. Mitochondria and Cancer: past, present and future. 2013;2013:Article ID 612369.Google Scholar
  2. 2.
    Finkel T. Oxygen radicals and signaling. Curr Opin Cell Biol. 1998;10:248–53.PubMedGoogle Scholar
  3. 3.
    Sena LA, Chandel NS. Mol Cell. 2012;48:158–67.PubMedCentralPubMedGoogle Scholar
  4. 4.
    Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol. 2003;552:335–44.Google Scholar
  5. 5.
    Adam-Vizi V, Chinopoulos C. Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol Sci. 2006;27:639–45Google Scholar
  6. 6.
    Altenhofer S, Kleikers PW, Radermacher KA, Scheurer P, Rob Hermans JJ, Schiffers P, Ho H, Wingler K, Schmidt HH. The NOX toolbox: validating the role of NADPH oxidase in physiology and disease. Cell Mol Life Sci. 2012;69:2327–43.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Damico R, Zulueta JJ, Hassoun PM. Pulmonary endothelial cell NOX. Am J Respir Cell Mol Biol. 2012;47:129–39.PubMedGoogle Scholar
  8. 8.
    Pendyala S, Natarajan V. Redox regulation of Nox proteins. Respir Physiol Neurobiol. 2010;174:265–71.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Briger K, Schiavone S, Miller Jr FJ, Krause K-H. Reactive oxygen species: from health and disease. Swiss Med Wkly. 2012;142:w13659.Google Scholar
  10. 10.
    Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol. 2003;552: 335–44.PubMedCentralPubMedGoogle Scholar
  11. 11.
    Poyton RO, Ball KA, Castello PR. Mitochondrial generation of free radicals and hypoxic signaling. Trends Endocrinol Metab. 2009;20:332–40.PubMedGoogle Scholar
  12. 12.
    Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417: 1–13.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Carnesecchi S, Pache JC, Barazzone-Argiroffo C. NOX enzymes: potential treatment for the treatment of acute lung injury. Cell Mol Life Sci. 2012;69:2373–85.PubMedGoogle Scholar
  14. 14.
    Castello PR, et al. Mitochondrial cytochrome oxidase produces nitric oxide under hypoxic conditions: implications for oxygen sensing and hypoxic signaling in eukaryotes. Cell Metab. 2006;3:277–87.PubMedGoogle Scholar
  15. 15.
    Baker PR, Schopfer FJ, O’Donnell VB, Freeman BA. Convergence of nitric oxide and lipid signaling: anti-inflammatory nitro-fatty acids. Free Radic Biol Med. 2009;46:989–1003.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Kansanen E, Jyrkkanen HK, Levonen AL. Activation of stress signaling pathways by electrophilic oxidized and nitrated lipids. Free Radic Biol Med. 2012;52:973–82.PubMedGoogle Scholar
  17. 17.
    Burgoyne JR, Rudy KO, Mayr M, Eaton P. Nitrosative protein oxidation is modulated during early endotoxemia. Nitric Oxide. 2011;25:118–24.PubMedCentralPubMedGoogle Scholar
  18. 18.
    Kudin AP, et al. Characterization of superoxide-producing sites in isolated brain mitochondria. J Biol Chem. 2004;279:4127–35.PubMedGoogle Scholar
  19. 19.
    Lambert AJ, et al. Superoxide production by NADH:ubiquinone oxidoreductase (complex I) depends on pH gradient across the mitochondrial inner membrane. Biochem J. 2004;382:511–7.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Brand MD. The sites and topology of mitochondrial superoxide production. Exp Gerontol. 2010;45:466–72.PubMedCentralPubMedGoogle Scholar
  21. 21.
    Ghafourifar P, Richter C. Nitric oxide synthase activity in mitochondria. FEBS Lett. 1997;418:291–6.PubMedGoogle Scholar
  22. 22.
    Giulivi C, Poderoso JJ, Boveris A. Production of nitric oxide by mitochondria. J Biol Chem. 1998;273:11038–43.PubMedGoogle Scholar
  23. 23.
    Lacza Z, Snipes JA, Zhang J, Horvath EM, Figueroa JP, Szabo C, Busija DW. Mitochondrial nitric oxide synthase is not eNOS, nNOS or iNOS. Free Radic Biol Med. 2003;35:1217–28.PubMedGoogle Scholar
  24. 24.
    Bolisetty S, Jaimes EA. Mitochondria and reactive oxygen species: physiology and pathophysiology. Int J Mol Sci. 2013;14:6306–44.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Piantadosi CA, Sukliman HB. Redox regulation of mitochondrial biogenesis. Free Radic Biol Med. 2012;53:2043–53.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Bourens M, Fontanesi F, Soto IC, Liu J, Barrientos A. Redox and reactive oxygen species regulation of mitochondrial cytochrome c oxidase biogenesis. Antioxid Redox Signal. 2012. doi: 10.1089/ars.2012.4847.PubMedGoogle Scholar
  27. 27.
    Okado-Matsumoto A, Fridovich I. Subcellular distribution of superoxide dismutase (SOD) in rat liver: Cu,Zn-SOD in mitochondria. J Biol Chem. 2001;276:38388–93.PubMedGoogle Scholar
  28. 28.
    Li Y, Huang TT, Carlson EJ, Melov S, Ursell PC, Olson JL, Noble LJ, Yoshimura MP, Berger C, Chan PH, et al. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet. 1996;11:376–81.Google Scholar
  29. 29.
    Madamanchi NR, Runge MS. Mitochondrial dysfunction in atherosclerosis. Circ Res. 2007;100:460–73.PubMedGoogle Scholar
  30. 30.
    Nicholls P. Classical catalase: ancient and modern. Arch Biochem Biophys. 2012;525: 95–101.PubMedGoogle Scholar
  31. 31.
    Ho YS, et al. Mice lacking catalase develop normally but show differential sensitivity to oxidant tissue injury. J Biol Chem. 2004;279:32804–12.PubMedGoogle Scholar
  32. 32.
    Flohe L, Schlegel W. Glutathione peroxidase. 1V. Intracellular distribution of the glutathione peroxidase system in rat the rat liver. Hoppe Seylers Z Physiol Chem. 1971;352:1401–10.PubMedGoogle Scholar
  33. 33.
    Singh AK, Dhaunsi GS, Gupta MP, Orak JK, Asayama K, Singh I. Demonstration of glutathione peroxidase in rat liver peroxisomes and its intraorganellar distribution. Arch Biochem Biophys. 1994;315:331–8.PubMedGoogle Scholar
  34. 34.
    Sies H, Sharov VS, Klotz LO, Briviba K. Glutathione peroxidase protects against peroxynitrite-mediated oxidations. A new function for selenoproteins as peroxynitrite reductase. J Biol Chem. 1997;272:27812–7.PubMedGoogle Scholar
  35. 35.
    Fu Y, Sies H, Lei XG. Opposite roles of selenium-dependent glutathione peroxidase-1 in superoxide generator doquat- and peroxynitrite-induced apoptosis and signaling. J Biol Chem. 2001;276:43004–9.PubMedGoogle Scholar
  36. 36.
    Imai H, et al. Early embryonic lethality caused by targeted disruption of the mouse PHGPx gene. Biochem Biophys Res Commun. 2003;305:278–86.PubMedGoogle Scholar
  37. 37.
    Yoshida T, et al. Glutathione peroxidase knockout mice are susceptible to myocardial ischemia reperfusion injury. Circulation. 1997;96 Suppl 9:II-216–20.Google Scholar
  38. 38.
    Nakamura H, Nakamura K, Yodoi J. Redox regulation of cellular activation. Annu Rev Immunol. 1997;15:351–69.PubMedGoogle Scholar
  39. 39.
    Miranda-Vizuette A, Damdimopoulos AE, Spyrou G. The mitochondrial thioredoxin system. Antioxid Redox Signal. 2000;2:801–10.Google Scholar
  40. 40.
    Hansen JM, Go YM, Jones DP. Nuclear and mitochondrial compartmentation of oxidative stress and redox signaling. Annu Rev Pharmacol Toxicol. 2006;46:215–34.PubMedGoogle Scholar
  41. 41.
    Wood ZA, Schroder E, Robin Harris J, Poole LB. Structure, mechanism and regulation of peroxiredoxins. Trends Biochem Sci. 2003;28:32–40.PubMedGoogle Scholar
  42. 42.
    Rhee SG, Chae HZ, Kim K. Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling. Free Radic Biol Med. 2005;38: 1543–52.PubMedGoogle Scholar
  43. 43.
    Vogel R, Wiesinger H, Hamprecht B, Dringen R. The regeneration of reduced glutathione in rat forebrain mitochondria identifies metabolic pathways providing the NADPH required. Neurosci Lett. 1999;275:97–100.PubMedGoogle Scholar
  44. 44.
    Tischler ME, Hecht P, Williamson JR. Effect of ammonia on mitochondrial and cytosolic NADH and NADPH systems in isolated rat-liver cells. FEBS Lett. 1977;76:99–104.PubMedGoogle Scholar
  45. 45.
    Griffith OW, Meister A. Origin and turnover of mitochondrial glutathione. Proc Natl Acad Sci U S A. 1985;82:4668–72.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Matsushima S, Ide T, Yamato M, Matsusaka H, Hattori F, Ikeuchi M, Kubota T, Sunagawa K, Hasegawa Y, Kurihara T, et al. Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice. Circulation. 2006;113:1779–86.PubMedGoogle Scholar
  47. 47.
    Ma Q. Role of Nrf2 in oxidative stress and toxicity. Ann Rev Pharmacol Toxicol. 2013;53: 401–20.Google Scholar
  48. 48.
    Imhoff BR, Hansen JM. Extracellular redox status regulates Nrf2 activation through mitochondrial reactive oxygen species. Biochem J. 2009;424:491–500.PubMedGoogle Scholar
  49. 49.
    Kobayashi M, Yamamoto M. Molecular mechanisms activating Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid Redox Signal. 2005;7:385–94.PubMedGoogle Scholar
  50. 50.
    Hansen JM, Zhang H, Jones DP. Mitochondrial thioredoxin-2 has a key role in determining tumor necrosis factor-α-induced reactive oxygen species generation, NF-kB activation, and apoptosis. Toxicol Sci. 2006;91:643–50.PubMedGoogle Scholar
  51. 51.
    Blander G, Guarente L. The Sir2 family of protein deacetylases. Annu Rev Biochem. 2004;73:417–35.PubMedGoogle Scholar
  52. 52.
    Verdin E, Hirschey MD, Finley LW, Haigis MC. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci. 2010;35:669–75.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004;303:2011–5.PubMedGoogle Scholar
  54. 54.
    Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, Bultsma Y, McBurney M, Guarente L. Mammalian SIRT1 represses forkhead transcription factors. Cell. 2004;116: 551–63.PubMedGoogle Scholar
  55. 55.
    van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Medema RH, Burgering BM. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem. 2004;279:28873–9.PubMedGoogle Scholar
  56. 56.
    Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005;434:113–8.PubMedGoogle Scholar
  57. 57.
    St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S, Handschin C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006;127:397–408.PubMedGoogle Scholar
  58. 58.
    Lee JH, Song MY, Song EK, Kim EK, Moon WS, Han MK, Park JW, Kwon KB, Park BH. Overexpression of SIRT1 protects pancreatic beta-cells against cytokine toxicity by suppressing the nuclear factor-kappaB signaling pathway. Diabetes. 2009;58:344–51.PubMedCentralPubMedGoogle Scholar
  59. 59.
    Qiu X, Brown K, Hirschey MD, Verdin E, Chen D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 2010;12:662–7.PubMedGoogle Scholar
  60. 60.
    Sack MN. Emerging characterization of the role of SIRT3-mediated mitochondrial protein deacetylation in the heart. Am J Physiol Heart Circ Physiol. 2011;301:H2191–7.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Alfadda AA, Sallam RM. Reactive oxygen species in health and disease. J Biomed Biotechnol. 2012. Article ID 936486, 14 p. doi: 10.1155/2012/936486.
  62. 62.
    Smith RAJ, Murphy MP. Animal and human studies with the mitochondria-targeted antioxidant MitoQ. Ann NY Acad Sci. 2010;1201:96–103.PubMedGoogle Scholar
  63. 63.
    Kelso GF, Porteous CM, Coulter CV, Hughes G, Porteous WK, Ledgerwood EC, et al. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and anti-apoptotic properties. J Biol Chem. 2001;276:4588–96.PubMedGoogle Scholar
  64. 64.
    Adlam VJ, et al. Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury. FASEB J. 2005;19:1088–95.PubMedGoogle Scholar
  65. 65.
    Neuzil J, et al. Mitochondria transmit apoptosis signalling in cardiomyocyte-like cells and isolated hearts exposed to experimental ischemia-reperfusion injury. Redox Rep. 2007;12: 148–62.PubMedGoogle Scholar
  66. 66.
    Lowes DA, Thottakam BMV, Webster NR, Murphy MP, Galley HF. The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis. Free Radic Biol Med. 2008;45:1559–65.PubMedGoogle Scholar
  67. 67.
    Lowes DA, Webster NR, Murphy MP, Galley HF. Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. Br J Anaesth. 2013;110:472–80.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Supinski GS, Murphy MP, Callahan LA. MitoQ administration prevents endotoxin-induced cardiac dysfunction. Am J Physiol Regul Integr Comp Physiol. 2009;297:R1095–102.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Mukhopadhyay P, Horvath B, Zsengeller Z, Zielonka J, Tanchian G, Holovac E, Kechrid M, Patel V, Stillman IE, Parikh SM, Joseph J, Kalyanaraman B, Pacher P. Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy. Free Radic Biol Med. 2012;52:497–506.PubMedCentralPubMedGoogle Scholar
  70. 70.
    Starenki D, Park J-I. Mitochondria-targeted nitroxide, Mito-CP, suppresses medullary thyroid carcinoma cell survival in vitro and in vivo. J Clin Endocrinol Metab. 2013;98:1529–40.PubMedCentralPubMedGoogle Scholar
  71. 71.
    Cunniff B, Benson K, Stumpff J, Newick K, Held P, Taatjes D, Joseph J, Kalyanaraman B, Heintz NH. Mitochondrial-targeted nitroxides disrupt mitochondrial architecture and inhibit expression of peroxiredoxins 3 and FOXM1 in malignant mesothelioma cells. J Cell Physiol. 2013;228:835–45.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Du J, Cullen JJ, Buettner GR. Ascorbic acid; chemistry, biology and the treatment of cancer. Biochim Biophys Acta. 2012;1826:443–57.PubMedCentralPubMedGoogle Scholar
  73. 73.
    Skulachev VP. A biochemical approach to the problem of aging: “megaproject” on membrane-penetrating ions. The first results and prospects. Biochemistry (Mosc). 2007;72:1385–96.Google Scholar
  74. 74.
    Bakeeva LE, Barskov IV, Isaev NK, Kapelko VI, Kazachenko AV, et al. Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 2. Treatment of some ROS- and age-related diseases (heart arrhythmia, heart infarctions, kidney ischemia, and stroke). Biochemistry (Mosc). 2008;73:1288–99.Google Scholar
  75. 75.
    Neroev VV, Archipova MM, Bakeeva LE, Fursova A, Grigorian EN, et al. Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of aging program. 4. Age-related eye disease. SkQ1 returns vision to blind animals. Biochemistry (Mosc). 2008;73: 1317–28.Google Scholar
  76. 76.
    Zhao K, Zhao GM, Wu D, et al. Cell permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death and reperfusion injury. J Biol Chem. 2008;279:34682–90.Google Scholar
  77. 77.
    Szeto HH. Cell-permeable, mitochondrial-targeted, peptide antioxidants. AAPS J. 2006;8: E521–31.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Petri S, Kiaei M, Damiano M, Hiller A, Willlie E, Manfredi G, et al. Cell-permeable peptide antagonists as a novel therapeutic approach in a mouse model of amyotrophic lateral sclerosis. J Neurochem. 2006;98:1141–8.PubMedGoogle Scholar
  79. 79.
    Szeto HH. Mitochondria-targeted cytoprotective peptides for ischemia-reperfusion injury. Antioxid Redox Signal. 2008;10:601–19.Google Scholar
  80. 80.
    Zhao K, Luo G, Giannelli S, Szeto HH. Mitochondria targeted peptide prevents mitochondrial depolarization and apoptosis induced by tert-butyl hydroperoxide in neuronal cell lines. Biochem Pharmacol. 2005;70:1796–806.PubMedGoogle Scholar
  81. 81.
    Cho J, Won K, Wu D, Soong Y, Liu S, Szeto HH, et al. Potent mitochondria-targeted peptides reduce myocardial infarction in rats. Coron Artery Dis. 2007;18:215–20.PubMedGoogle Scholar
  82. 82.
    Song W, Shin J, Lee J, Kim H, Oh D, Edelberg JM, et al. A potent opiate agonist protects against myocardial stunning during myocardial ischemia and reperfusion in rats. Coron Artery Dis. 2005;16:407–10.PubMedGoogle Scholar
  83. 83.
    Jiang J, Kurnikov I, Belikova NA, Xiao J, Zhao Q, Amoscato AA, et al. Structural requirements for optimized delivery, inhibition of oxidative stress, and antiapoptotic activity of targeted nitroxides. J Pharmacol Exp Ther. 2007;320:1050–60.PubMedGoogle Scholar
  84. 84.
    Wipf P, Xiao J, Jiang J, Belikova NA, Tyurin VA, Fink MP, et al. Mitochondrial targeting of selective electron scavengers: synthesis and biological analysis of hemigramicidin-TEMPO conjugates. J Am Chem Soc. 2005;127:12460–1.PubMedGoogle Scholar
  85. 85.
    Jiang J, Belikova NA, Hoye AT, Zhao Q, Epperly MW, Greenberger JS, et al. A mitochondria-targeted nitroxide/hemigramicidin S conjugate protects mouse embryonic cells against gamma irradiation. Int J Radiat Oncol Biol Phys. 2008;70:816–25.PubMedCentralPubMedGoogle Scholar
  86. 86.
    Rajagopalan MS, Gupta K, Epperly MW, Franicola D, Zhang X, Wang H, et al. The mitochondria-targeted nitroxide JP4-039 augments potentially lethal irradiation damage repair. In Vivo. 2009;23:717–26.PubMedCentralPubMedGoogle Scholar
  87. 87.
    Vanhorebeek I, De Vos R, Mesotten D, et al. Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet. 2005;365:53–9.PubMedGoogle Scholar
  88. 88.
    White RR, Mela L, Bacalzo Jr LV, et al. Hepatic ultrastructure in endotoxemia, hemorrhage, and hypoxia: emphasis on mitochondrial changes. Surgery. 1973;73:525–34.PubMedGoogle Scholar
  89. 89.
    Connell RS, Harrison MW, Mela-Riker L, et al. Quantitative ultrastructure of skeletal and cardiac muscle hyperdynamic sepsis. Prog Clin Biol Res. 1988;264:325–32.PubMedGoogle Scholar
  90. 90.
    Welty-Wolf KE, Simonson SG, Huang YC, et al. Ultrastructural changes in skeletal muscle mitochondria in gram-negative sepsis. Shock. 1996;5:378–84.PubMedGoogle Scholar
  91. 91.
    Crouser ED, Julian MW, Blaho DV, et al. Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med. 2002;30:276–84.PubMedGoogle Scholar
  92. 92.
    Harrois A, Huet O, Duranteau J. Alterations of mitochondrial function in sepsis and critical illness. Curr Opin Anaesthesiol. 2009;22:143–9.PubMedGoogle Scholar
  93. 93.
    Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, Singer M. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet. 2002;360:219–23.PubMedGoogle Scholar
  94. 94.
    Rowlands DJ, et al. Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determine the severity of inflammation in mouse lung microvessels. J Clin Invest. 2011;121:1986–99.PubMedCentralPubMedGoogle Scholar
  95. 95.
    Dada LA, Sznajder JI. Mitochondrial Ca2+ and ROS take center stage to orchestrate TNF-α mediated inflammatory responses. J Clin Invest. 2011;121:1683–5.PubMedCentralPubMedGoogle Scholar
  96. 96.
    Weiss DJ, Kolls JK, Oritz LA, Panoskaltsis-Mortari A, Prockop DJ. Stem cells and cell therapies in lung biology and lung diseases. Proc Am Thorac Soc. 2008;5:637–67.PubMedCentralPubMedGoogle Scholar
  97. 97.
    Matthay MA, Goolaerts A, Howard JP, Lee JW. Mesenchymal stem cells for acute lung injury: preclinical evidence. Crit Care Med. 2010;38:S569–73.PubMedCentralPubMedGoogle Scholar
  98. 98.
    Islam MN, Das SR, Emin MT, Wei M, Sun L, Westphalen K, Rowlands DJ, Quadri SK, Bhattacharya S, Bhattacharya J. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med. 2012;18:759–65.PubMedCentralPubMedGoogle Scholar
  99. 99.
    Wood LG, Gibson PG, Garg ML. Biomarkers of lipid peroxidation, airway inflammation, and asthma. Eur Respir J. 2003;21:177–86.PubMedGoogle Scholar
  100. 100.
    Heinzmann A, Thoma C, Dietrich H, Deichmann KA. Identification of common polymorphisms in the mitochondrial genome. Allergy. 2003;58:830–1.PubMedGoogle Scholar
  101. 101.
    Raby BA, Klanderman B, Murphy A, Mazza S, Camargo Jr CA, Silverman EK, Weiss ST. A common mitochondrial haplogroup is associated with elevated total serum IgE levels. J Allergy Clin Immunol. 2007;120:351–8.PubMedGoogle Scholar
  102. 102.
    Zifa E, Daniil Z, Skoumi E, Stavrou M, Papadimitriou K, Terzenidou M, Kostikas K, Bagiatis V, Gourgoulianis KI, Mamuris Z. Mitochondrial genetic background plays a role in increasing risk to asthma. Mol Biol Rep. 2012;39:4697–708.PubMedGoogle Scholar
  103. 103.
    Servais S, Boussouar A, Molnar A, Douki T, Pequignot JM, Favier R. Age-related sensitivity to lung oxidative stress during ozone exposure. Free Radic Res. 2005;39:305–16.PubMedGoogle Scholar
  104. 104.
    Fahn HJ, Wang LS, Kao SH, Chang SC, Huang MH, Wei YH. Smoking –associated mitochondrial DNA mutations and lipid peroxidation in human lung tissues. Am J Respir Cell Mol Biol. 1998;19:901–19.PubMedGoogle Scholar
  105. 105.
    Reddy PH. Mitochondrial dysfunction and oxidative stress in asthma: implications for mitochondria-targeted antioxidant therapeutics. Pharmaceuticals (Basel). 2011;25:429–56.Google Scholar
  106. 106.
    Comhair SA, Ricci KS, Arroliga M, Lara AR, Dweik RA, Song W, Hazen SL, Bleecker ER, Busse WW, Chung KF, et al. Correlation of systemic superoxide dismutase deficiency to airflow obstruction in asthma. Am J Respir Crit Care Med. 2005;172:306–13.PubMedCentralPubMedGoogle Scholar
  107. 107.
    De Raeve HR, Thunnissen FB, Kaneko FT, Guo FH, Lewis M, Kavuru MS, Secic M, Thomassen MJ, Erzurum SC. Decreased Cu, Zn-SOD activity in asthmatic airway epithelium: correction by inhaled corticosteroid in vivo. Am J Physiol. 1997;272:L148–54.PubMedGoogle Scholar
  108. 108.
    Mabalirajan U, Dinda AK, Kumar S, Roshan R, Gupta P, Sharma SK, Ghosh B. Mitochondrial structural changes and dysfunction are associated with experimental allergic asthma. J Immunol. 2008;181:3540–8.PubMedGoogle Scholar
  109. 109.
    Hayashi T, Ishii A, Nakai S, Hasgawa K. Ultrastructure of goblet-cell metaplasia from Clara cell in the allergic asthmatic airway inflammation in a mouse model of asthma in vivo. Virchows Arch. 2004;444:66–73.PubMedGoogle Scholar
  110. 110.
    Konradova V, Copova C, Sukova B, Houstek J. Ultrastructure of the bronchial epithelium in three children with asthma. Pediatr Pulmonol. 1985;1:182–7.PubMedGoogle Scholar
  111. 111.
    Simoes DC, Psarra A-M G, Mauad T, Pantou I, Roussos C, Sekeris CE, Gratziou C. Glucocorticoid and estrogen receptors are reduced in mitochondria of lung epithelial cells in asthma. PLoS One. 2012;7:e39183.PubMedCentralPubMedGoogle Scholar
  112. 112.
    Ueda S, Masutani H, Nakamura H, Tanaka T, Ueno M, et al. Redox control of cell death. Antioxid Redox Signal. 2002;4:405–14.PubMedGoogle Scholar
  113. 113.
    Sionov RV, Cohen O, Kfir S, Zilberman Y, Yefenof E. Role of mitochondrial glucocorticoid receptor in glucocorticoid-induced apoptosis. J Exp Med. 2006;203:189–201.PubMedCentralPubMedGoogle Scholar
  114. 114.
    Du J, Wang Y, Hunter R, Wei Y, Blumenthal R, et al. Dynamic regulation of mitochondrial function by glucocorticoids. Proc Natl Acad Sci U S A. 2009;106:3543–8.PubMedCentralPubMedGoogle Scholar
  115. 115.
    Catley MC, Birrell MA, Hardaker EL, de Alba J, Farrow S, et al. Estrogen receptor beta: expression profile and possible anti-inflammatory role in disease. J Pharmacol Exp Ther. 2008;326:83–8.PubMedGoogle Scholar
  116. 116.
    Aguilera-Aguirre L, Bacsi A, Saavedra-Molina A, Kurosky A, Sur S, Boldogh I. Mitochondrial dysfunction increases allergic airway inflammation. J Immunol. 2009;183:5379–87.PubMedCentralPubMedGoogle Scholar
  117. 117.
    Montezano AC, Touyz RM. Molecular mechanisms of hypertension – reactive oxygen species and antioxidants: a basic science update for the clinician. Can J Cardiol. 2012;28:288–95.PubMedGoogle Scholar
  118. 118.
    Tabima DM, Frizzell S, Gladwin MT. Reactive oxygen and nitrogen species in pulmonary hypertension. Free Radic Biol Med. 2012;52:1970–86.PubMedGoogle Scholar
  119. 119.
    Archer SL, Gomberg-Maitland M, Maitland ML, Rich S, Garcia JGN, Weir EK. Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1α-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer. Am J Physiol Heart Circ Physiol. 2008;294:H570–8.PubMedGoogle Scholar
  120. 120.
    McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Linder JR, Mathier MA, Mcgoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J, Harrington RA, Anderson JL, Bates ER, Bridges CR, Eisenberg MJ, Ferrari VA, Grines CL, Hlatky MA, Jacobs AK, Kaul S, Lichtenberg RC, Moliterno DJ, Mukherjee D, Pohost GM, Schofield RS, Shubrooks SJ, Stein JH, Tracy CM, Weitz HH, Wesley DJ. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation. 2009;119: 2250–94.PubMedGoogle Scholar
  121. 121.
    Michelakis ED, Wilkins MR, Rabinovitch M. Emerging concepts and translational priorities in pulmonary arterial hypertension. Circulation. 2008;118:1486–95.PubMedGoogle Scholar
  122. 122.
    Sutendra G, Dromparis P, Wright P, Bonnet S, Haromy A, Hao Z, McMurtry MS, Michalak M, Vance JE, Sessa WC, Michelakis ED. The role of Nogo and the mitochondria-endoplasmic reticulum unit in pulmonary hypertension. Sci Transl Med. 2011;3(88):88ra55.PubMedCentralPubMedGoogle Scholar
  123. 123.
    Wolin MS, Ahmad M, Gupte SA. The source of oxidative stress in the vessel wall. Kidney Int. 2005;67:1659–61.PubMedGoogle Scholar
  124. 124.
    Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC, Dyck JR, Gomberg-Maitland M, Thebaud B, Husain AN, Cipriani N, Rehman J. Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation. 2010;121:2661–71.PubMedCentralPubMedGoogle Scholar
  125. 125.
    Sharma S, Sud N, Wiseman DA, Carter AL, Kumar S, Hou Y, Rau T, Wilham J, Harmon C, Oishi P, Fineman JR, Black SM. Altered carnitine homeostasis is associated with decreased mitochondrial function and altered nitric oxide signaling in lambs with pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2008;294:L46–56.PubMedCentralPubMedGoogle Scholar
  126. 126.
    Xue C, Johns RA. Endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995;333:1642–4.PubMedGoogle Scholar
  127. 127.
    Hu W, Jin R, Zhang J, You T, Peng Z, Ge X, Bronson RT, Halperin JA, Loscalzo J, Qin X. The critical roles of platelets activation and reduced NO bioavailability in fatal pulmonary arterial hypertension in a murine hemolysis model. Blood. 2010;116:1613–22.PubMedCentralPubMedGoogle Scholar
  128. 128.
    Selman M, King TE, Pardo A, American Thoracic Society, European Respiratory Society, American College of Chest Physicians. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134:136–51.PubMedGoogle Scholar
  129. 129.
    Wynn TA. Integrating mechanisms of pulmonary fibrosis. J Exp Med. 2011;208:1339–50.PubMedCentralPubMedGoogle Scholar
  130. 130.
    He X, Young S-H, Schwegler-Berry D, Chisholm WP, Fernback JE, Ma Q. Multiwalled carbon nanotubes induce a fibrogenic response by stimulating reactive oxygen species production, activating NF-kB signaling and promoting fibroblast-to-myofibroblast transformation. Chem Res Toxicol. 2011;24:2237–48.PubMedGoogle Scholar
  131. 131.
    Noble PW, Barkauskas CE, Jiang D. Pulmonary fibrosis: patterns and perpetrators. J Clin Invest. 2012;122:2756–62.PubMedCentralPubMedGoogle Scholar
  132. 132.
    Cheresh P, Kim S-J, Tulsiram S, Kamp DW. Oxidative stress and pulmonary fibrosis. Biochim Biophys Acta. 2013;1832:1028–40.Google Scholar
  133. 133.
    Tatler AL, Jenkins G. Proc Am Thorac Soc. 2012;9:130–6. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214:199–210.Google Scholar
  134. 134.
    Sakai N, Tager AM. Fibrosis of two: epithelial cell-fibroblast interactions in pulmonary fibrosis. Biochim Biophys Acta. 2013;1832:911–21.PubMedCentralPubMedGoogle Scholar
  135. 135.
    Cheresh P, Kim S-J, Tulsiram S, Kamp DW. Oxidative stress and pulmonary fibrosis. Biochim Biophys Acta. 2013;1832:1028–40.PubMedCentralPubMedGoogle Scholar
  136. 136.
    Crestani B, Besnard J, Boczkowski J. Signalling pathways from NADPH oxidase-4 to idiopathic pulmonary fibrosis. Int J Biochem Cell Biol. 2011;43:1086–9.PubMedGoogle Scholar
  137. 137.
    Hecker L, Vittal R, Jones T, Jagirdar R, Luckhardt TR, Horowitz JC, Pennathur S, Martinez FJ, Thannickal VJ. NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med. 2009;15:1077–81.PubMedCentralPubMedGoogle Scholar
  138. 138.
    Osborn-Heaford HL, Ryan AJ, Murthy S, Racila AM, He C, Sieren JC, Spitz DR, Carter AB. Mitochondrial Rac1 import and electron transfer from cytochrome c is required for pulmonary fibrosis. J Biol Chem. 2012;287:3301–12.PubMedCentralPubMedGoogle Scholar
  139. 139.
    He C, Murthy S, McCormick ML, Spitz DR, Ryan AJ, Carter AB. Mitochondrial Cu, Zn-superoxide dismutase mediates pulmonary fibrosis by augmenting H2O2 generation. J Biol Chem. 2011;286:15597–607.PubMedCentralPubMedGoogle Scholar
  140. 140.
    Murthy S, Adamcakova-Dodd A, Perry SS, Tephly LA, Keller RM, Metwali N, Meyerholz DK, Wang Y, Glogauer M, Thorne PS, Carter AB. Modulation of reactive oxygen species by Rac1 or catalase prevents asbestos-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2009;297:L846–55.PubMedCentralPubMedGoogle Scholar
  141. 141.
    Tanjore H, Blackwell TS, Lawson WE. Emerging evidence for endoplasmic reticulum stress in the pathogenesis of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2012;302:L721–9.PubMedCentralPubMedGoogle Scholar
  142. 142.
    de Brito OM, Scorrano L. An intimate liaison: spatial organization of the endoplasmic reticulum mitochondria relationship. EMBO J. 2008;29:2715–23.Google Scholar
  143. 143.
    Liu RM, Gaston KA, Pravia XX. Oxidative stress and glutathione in TGF-beta-mediated fibrogenesis. Free Radic Biol Med. 2010;48:1–15.PubMedCentralPubMedGoogle Scholar
  144. 144.
    Jain M, Rivera S, Monclus EA, Synenki L, Zirk A, Eisenbart J, Feghali-Bostwick C, Mutlu GM, Budinger GRS, Chandel NS. Mitochondrial reactive oxygen species regulate transforming growth factor-β signaling. J Biol Chem. 2013;288:770–7.PubMedCentralPubMedGoogle Scholar
  145. 145.
    Baraldi E, Filippone M. Chronic lung disease after birth. N Engl J Med 2007;357:1946–55.Google Scholar
  146. 146.
    Ratner V, Starkov A, Matsiukevich D, Polin RA, Ten VS. Mitochondrial dysfunction contributes to alveolar development arrest in hyperoxia-exposed mice. Am J Respir Cell Mol Biol. 2009;40:511–8.PubMedCentralPubMedGoogle Scholar
  147. 147.
    Northway Jr WH, Rosan RC. Radiographic features of pulmonary oxygen toxicity in the newborn: bronchopulmonary dysplasia. Radiology. 1968;91:49–58.PubMedGoogle Scholar
  148. 148.
    Saugstad OD. Bronchopulmonary dysplasia and oxidative stress: are we closer to an understanding of the pathogenesis of BPD? Acta Paediatr. 1997;86:1277–82.PubMedGoogle Scholar
  149. 149.
    Yoneda M, Katsumata K, Hayakawa M, Tanaka M, Ozawa T. Oxygen stress induces an apoptotic cell death associated with fragmentation of mitochondrial genome. Biochem Biophys Res Commun. 1995;209:723–9.PubMedGoogle Scholar
  150. 150.
    Li J, Gao X, Qian M, Eaton JW. Mitochondrial metabolism underlies hyperoxic cell damage. Free Radic Biol Med. 2004;36:1460–70.PubMedGoogle Scholar
  151. 151.
    Budinger GRS, Mutlu GM, Urich D, Soberanes S, Buccellato LJ, Hawkins K, Chiarella SE, Radigan KA, Eisenbart J, Agrawal H, Berkelhamer S, Hekimi S, Zhang J, Periman H, Schumacker PT, Jain M, Chandel NS. Am J Respir Crit Care Med. 2011;183:1043–54.PubMedCentralPubMedGoogle Scholar
  152. 152.
    Budinger GRS, Tso M, McClintock, Dean DA, Sznajder JI, Chandel NS. Hyperoxia-induced apoptosis does not require mitochondrial reactive oxygen species and is regulated by Bcl-2 proteins. J Biol Chem. 2002;277:15654–60.PubMedGoogle Scholar
  153. 153.
    Brueckl C, Kaestle S, Kerem A, Habazettl H, Krombach F, Kuppe H, Kuebler WM. Hyperoxia-induced reactive oxygen species formation in pulmonary capillary endothelial cells in situ. Am J Respir Cell Mol Biol. 2006;34:453–63.PubMedGoogle Scholar
  154. 154.
    Parinandi NL, Kleinberg MA, Usatyuk PV, Cummings RJ, Pennathur A, Cardounel AJ, Zweier JL, Garcia JGN, Natarajan V. Hyperoxia-induced NAD(P)H oxidase activation and regulation by MAP kinases in human lung endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2003;284:L26–38.PubMedGoogle Scholar
  155. 155.
    Asikainen TM, White CW. Antioxidant defenses in the preterm lung: role for hypoxia-inducible factors in BPD? Toxicol Appl Pharmacol. 2005;203:177–88.Google Scholar
  156. 156.
    Yee M, Vitiello PF, Roper JM, Staversky RJ, Wright TW, McGrath-Morrow SA, et al. Type II epithelial cells are critical target for hyperoxia-mediated impairment of postnatal lung development. Am J Physiol Lung Cell Mol Physiol. 2006;291:L1101–11.PubMedGoogle Scholar
  157. 157.
    Warner BB, Stuart LA, Papes RA, Wispe JR. Functional and pathological effects of prolonged hyperoxia in neonatal mice. Am J Physiol. 1998;275:L110–7.PubMedGoogle Scholar
  158. 158.
    Frank L. Effects of oxygen on the newborn. Fed Proc. 1985;44:2328–34.PubMedGoogle Scholar
  159. 159.
    Berkelhamer SK, Kim GA, Radder JE, Wedgwood S, Czech L, Steinhorn RH, Schumacker PT. Developmental differences in hyperoxia-induced oxidative stress and cellular responses in the murine lung. Free Radic Biol Med. 2013;61:51–60.Google Scholar
  160. 160.
    Usatyuk PV, Gorshkova IA, He D, Zhao Y, Kalari SK, Garcia JG, Natarajan V. Phospholipase D-mediated activation of IQGAP1 through Rac1 regulates hyperoxia-induced p47phox translocation and reactive oxygen species generation in lung endothelial cells. J Biol Chem. 2009;284:15339–52.PubMedCentralPubMedGoogle Scholar
  161. 161.
    Zhang X, Shan P, Sasidhar M, Chupp GL, Flavell RA, Choi AM, Lee PJ. Reactive oxygen species and extracellular signal regulated kinase 1/2 mitogen activated protein kinase mediate hyperoxia-induced cell death in lung endothelium. Am J Respir Cell Mol Biol. 2003;28:305–15.PubMedGoogle Scholar
  162. 162.
    Troung SV, Monick MM, Yarovinsky TO, Powers LS, Nyunoya T, Hunnighake GW. Extracellular signal-regulated kinase activation delays hyperoxia-induced epithelial cell death in conditions of Akt downregulation. Am J Respir Cell Mol Biol. 2004;31:611–8.Google Scholar
  163. 163.
    Pendyala S, Usatyuk PV, Gorshkova IA, Garcia JG, Natarajan V. Regulation of NADPH oxidase in vascular endothelium: the role of phospholipases, protein kinases and cytoskeletal proteins. Antioxid Redox Signal. 2009;11:841–60.PubMedCentralPubMedGoogle Scholar
  164. 164.
    Singleton PA, Pendyala S, Gorshkova IA, Mambetsariev N, Moitra J, Garcia JG, Natarajan V. Dynamin 2 and c-Abl are novel regulators of hyperoxia-mediated NADPH oxidase activation and reactive oxygen species production in caveolin-enriched microdomains of the endothelium. J Biol Chem. 2009;284:34964–75.PubMedCentralPubMedGoogle Scholar
  165. 165.
    Harijith A, Pendyala S, Reddy NM, Bai T, Usatyuk PV, Berdyshev EV, Gorshkova I, Huang LS, Mohan V, Garzon S, Kanteti P, Reddy SP, Raj U, Natarajan V. Sphingosine Kinase 1 deficiency confers protection against hyperoxia-induced bronchopulmonary dysplasia in a murine model: role of S1P signaling and Nox proteins. Am J Pathol. 2013;183:1169–82.Google Scholar
  166. 166.
    Chen Y, Chang L, Li W, Rong Z, Liu W, Shan R, Pan R. Thioredoxin protects fetal type II epithelial cells from hyperoxia-induced injury. Pediatr Pulmonol. 2010;45:1192–200.PubMedGoogle Scholar
  167. 167.
    Conley KE, Jubrias SA, Amara CE, Marcinek DJ. Mitochondrial dysfunction; impact on exercise performance and cellular aging. Exerc Sport Sci Rev. 2007;35:43–9.PubMedGoogle Scholar
  168. 168.
    Schiff M, Benit P, Coulibaly A, Loublier S, El-Khoury R, Rustin P. Mitochondrial response to controlled nutrition in health and disease. Nutr Rev. 2011;69:65–75.PubMedGoogle Scholar
  169. 169.
    Cerqueira FM, Laurindo FR, Kowaltowski AJ. Mild mitochondrial uncoupling and calorie restriction increase fasting eNOS, akt, and mitochondrial biogenesis. PLoS One. 2011;6:e18433.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Harijith Anantha
    • 1
  • Prasad Kanteti
    • 2
  • Panfeng Fu
    • 2
  • Sainath R. Kotha
    • 3
  • Narasimham L. Parinandi
    • 4
  • Viswanathan Natarajan
    • 5
    Email author
  1. 1.Department of PediatricsUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Department of PharmacologyUniversity of Illinois at ChicagoChicagoUSA
  3. 3.Department of Internal MedicineWexner Medical Center, 201 Davis Heart and Lung Research InstituteColumbusUSA
  4. 4.Division of Allergy, Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, College of MedicineOhio State University Wexner Medical CenterColumbusUSA
  5. 5.Department of Pharmacology and MedicineUniversity of Illinois at ChicagoChicagoUSA

Personalised recommendations