Mitochondrion: A Missing Link in Asthma Pathogenesis

  • Ulaganathan Mabalirajan
  • Anurag Agrawal
  • Balaram GhoshEmail author
Part of the Respiratory Medicine book series (RM, volume 15)


Asthma is a multifactorial airway disease with airway hyperresponsiveness, airway inflammation, goblet cell metaplasia, and structural changes including airway smooth muscle proliferation and subepithelial fibrosis. Airway epithelial injury and apoptosis is an important triggering and amplification point in asthma pathogenesis, and mitochondrial dysfunction in epithelial cells appears to play an important role. On the other hand, mitochondrial biogenesis is an important aspect of smooth muscle hypertrophy and fibroblast proliferation, which leads to airway remodeling and hyperresponsiveness. In mice, preexisting mitochondrial dysfunction has been shown to potentiate allergic experimental asthma. In this review, we summarize the current understanding on the involvement of mitochondria in asthma pathogenesis, discuss the probable points of intersection between lung pathobiology and mitochondrial biology, and speculate regarding the road ahead. Mitochondrial influence on cellular oxidative and nitrative stress, apoptosis, and calcium homeostasis is covered in detail, as well as the role of molecules like nitric oxide synthase, asymmetric dimethyl arginine (ADMA), and peroxynitrite on mitochondrial function, epithelial injury, and asthma. Potential therapeutic strategies involving coenzyme Q, vitamin E, and esculetin that influence mitochondrial function and alleviate features of asthma are also discussed.


Asthma Mitochondria Mitochondrial dysfunction Apoptosis 


  1. 1.
    Ernster L, Schatz G. Mitochondria: a historical review. J Cell Biol. 1981;91:227–55.PubMedCentralGoogle Scholar
  2. 2.
    Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell. 2012;148:1145–59.PubMedGoogle Scholar
  3. 3.
    Chacinska A, Koehler CM, Milenkovic D, Lithgow T, Pfanner N. Importing mitochondrial proteins: machineries and mechanisms. Cell. 2009;138:628–44.PubMedCentralPubMedGoogle Scholar
  4. 4.
    Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007;87:99–163.PubMedGoogle Scholar
  5. 5.
    Crow MT, Mani K, Nam YJ, Kitsis RN. The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res. 2004;95:957–70.PubMedGoogle Scholar
  6. 6.
    Tal MC, Iwasaki A. Mitoxosome: a mitochondrial platform for cross-talk between cellular stress and antiviral signaling. Immunol Rev. 2011;243:215–34.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Masoli M, Fabian D, Holt S, Beasley R. Global Initiative for Asthma (GINA) program: the global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004;59:469–78.PubMedGoogle Scholar
  8. 8.
    Braman SS. The global burden of asthma. Chest. 2006;130:4S–12.PubMedGoogle Scholar
  9. 9.
    King CS, Moores LK. Clinical asthma syndromes and important asthma mimics. Respir Care. 2008;53:568–80.PubMedGoogle Scholar
  10. 10.
    The Global Asthma Report 2011. Paris: The International Union Against Tuberculosis and Lung Disease; 2011.Google Scholar
  11. 11.
    Agrawal A, Mabalirajan U, Ahmad T, Ghosh B. Emerging interface between metabolic syndrome and asthma. Am J Respir Cell Mol Biol. 2011;44:270–5. Review.PubMedGoogle Scholar
  12. 12.
    Fahy JV. Eosinophilic and neutrophilic inflammation in asthma: insights from clinical studies. Proc Am Thorac Soc. 2009;6:256–9.PubMedGoogle Scholar
  13. 13.
    Monteseirín J. Neutrophils and asthma. J Investig Allergol Clin Immunol. 2009;19:340–54.PubMedGoogle Scholar
  14. 14.
    Wang W, Li JJ, Foster PS, Hansbro PM, Yang M. Potential therapeutic targets for steroid-resistant asthma. Curr Drug Targets. 2010;11:957–70.PubMedGoogle Scholar
  15. 15.
    Tattersfield AE. The site of the defect in asthma. Neurohumoral, mediator or smooth muscle? Chest. 1987;91:184S–9.PubMedGoogle Scholar
  16. 16.
    Hirst SJ, Lee TH. Airway smooth muscle as a target of glucocorticoid action in the treatment of asthma. Am J Respir Crit Care Med. 1998;158:S201–6.PubMedGoogle Scholar
  17. 17.
    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
  18. 18.
    Hayashi T, Ishii A, Nakai S, Hasegawa 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
  19. 19.
    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
  20. 20.
    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
  21. 21.
    Gvozdjáková A, Kucharská J, Bartkovjaková M, Gazdíková K, Gazdík FE. Coenzyme Q10 supplementation reduces corticosteroids dosage in patients with bronchial asthma. Biofactors. 2005;25:235–40.PubMedGoogle Scholar
  22. 22.
    Fogarty A, Lewis S, Weiss S, Britton J. Dietary vitamin E, IgE concentration, and atopy. Lancet. 2000;356:1573–4.PubMedGoogle Scholar
  23. 23.
    Blesa S, Cortijo J, Mata M, Serrano A, Closa D, Santangelo F, et al. Oral N-acetylcysteine attenuates the rat pulmonary inflammatory response to antigen. Eur Respir J. 2003;21:394–400.PubMedGoogle Scholar
  24. 24.
    Gredilla R. DNA damage and base excision repair in mitochondria and their role in aging. J Aging Res. 2010;2011:257093.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet. 2005;6:389–402.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Ghosh B, Batra J, Sharma S, Kumar A, Sharma M, Chatterjee R, Mabalirajan U. Genetic components of asthma: current status and future goals. Int Rev Asthma (Jpn). 2006;8:67–88.Google Scholar
  27. 27.
    Kumar A, Ghosh B. Genetics of asthma: a molecular biologist perspective. Clin Mol Allergy. 2009;7:7.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Ober C, Hoffjan S. Asthma genetics 2006: the long and winding road to gene discovery. Genes Immun. 2006;7:95–100.PubMedGoogle Scholar
  29. 29.
    Oliveti JF, Kercsmar CM, Redline S. Pre- and perinatal risk factors for asthma in inner city African-American children. Am J Epidemiol. 1996;143:570–7.PubMedGoogle Scholar
  30. 30.
    Litonjua AA, Carey VJ, Burge HA, Weiss ST, Gold DR. Parental history and the risk for childhood asthma. Does mother confer more risk than father? Am J Respir Crit Care Med. 1998;158:176–81.PubMedGoogle Scholar
  31. 31.
    Soto-Quiros ME, Silverman EK, Hanson LA, Weiss ST, Celedon JC. Maternal history, sensitization to allergens, and current wheezing, rhinitis, and eczema among children in Costa Rica. Pediatr Pulmonol. 2002;33:237–43.PubMedGoogle Scholar
  32. 32.
    Kurukulaaratchy RJ, Matthews S, Arshad SH. Relationship between childhood atopy and wheeze: what mediates wheezing in atopic phenotypes? Ann Allergy Asthma Immunol. 2006;97:84–91.PubMedGoogle Scholar
  33. 33.
    Hamada K, Suzaki Y, Goldman A, Ning YY, Goldsmith C, Palecanda A, et al. Allergen-independent maternal transmission of asthma susceptibility. J Immunol. 2003;170:1683–9.PubMedGoogle Scholar
  34. 34.
    Liu CA, Wang CL, Chuang H, Ou CY, Hsu TY, Yang KD. Prediction of elevated cord blood IgE levels by maternal IgE levels, and the neonate’s gender and gestational age. Chang Gung Med J. 2003;26:561–9.PubMedGoogle Scholar
  35. 35.
    Raby BA, Klanderman B, Murphy A, Mazza S, Camargo Jr CA, Silverman EK, et al. A common mitochondrial haplogroup is associated with elevated total serum IgE levels. J Allergy Clin Immunol. 2007;120:351–8.PubMedGoogle Scholar
  36. 36.
    Clifton VL, Davies M, Moore V, Wright IM, Ali Z, Hodyl NA. Developmental perturbation induced by maternal asthma during pregnancy: the short- and long-term impacts on offspring. J Pregnancy. 2012;2012:741613. Epub 2012 Jul 8.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Zifa E, Daniil Z, Skoumi E, Stavrou M, Papadimitriou K, Terzenidou M, et al. Mitochondrial genetic background plays a role in increasing risk to asthma. Mol Biol Rep. 2012;39: 4697–708.PubMedGoogle Scholar
  38. 38.
    Schauberger EM, Ewart SL, Arshad SH, Huebner M, Karmaus W, Holloway JW, et al. Identification of ATPAF1 as a novel candidate gene for asthma in children. J Allergy Clin Immunol. 2011;128:753–60.PubMedCentralPubMedGoogle Scholar
  39. 39.
    Fukuda T, Mochida S, Fukushima Y, Makino S. Detection of allergen-induced genes in peripheral blood mononuclear cells of patients with allergic asthma using subtractive hybridization. J Allergy Clin Immunol. 1995;96:1076–82.PubMedGoogle Scholar
  40. 40.
    Polonikov AV, Ivanov VP, Solodilova MA, Kozhukhov MA, Panfilov VI, Bulgakova VI. Polymorphism -930A > G of the cytochrome b gene is a novel genetic marker of predisposition to bronchial asthma. Ter Arkh. 2009;81:31–5.PubMedGoogle Scholar
  41. 41.
    Schmuczerova J, Brdicka R, Dostal M, Sram RJ, Topinka J. Genetic variability of HVRII mtDNA in cord blood and respiratory morbidity in children. Mutat Res. 2009;666:1–7.PubMedGoogle Scholar
  42. 42.
    Jones M, Mitchell P, Wang JJ, Sue C. MELAS A3243G mitochondrial DNA mutation andage related maculopathy. Am J Ophthalmol. 2004;138:1051–3.PubMedGoogle Scholar
  43. 43.
    Shanske AL, Shanske S, Silvestri G, Tanji K, Wertheim D, Lipper S. MELAS point mutation with unusual clinical presentation. Neuromuscul Disord. 1993;3:191–3.PubMedGoogle Scholar
  44. 44.
    Finsterer J. Genetic, pathogenetic, and phenotypic implications of the mitochondrial A3243G tRNALeu(UUR)mutation. Acta Neurol Scand. 2007;116:1–14.PubMedGoogle Scholar
  45. 45.
    Marchetti P, Castedo M, Susin SA, Zamzami N, Hirsch T, Macho A, et al. Mitochondrial permeability transition is a central coordinating event of apoptosis. J Exp Med. 1996;184: 1155–60.PubMedGoogle Scholar
  46. 46.
    Elias JA, Zhu Z, Chupp G, Homer RJ. Airway remodeling in asthma. J Clin Invest. 1999;104:1001–6.PubMedCentralPubMedGoogle Scholar
  47. 47.
    Elias JA, Lee CG, Zheng T, Ma B, Homer RJ, Zhu Z. New insights into the pathogenesis of asthma. J Clin Invest. 2003;111:291–7.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Konga DB, Kim Y, Hong SC, Roh YM, Lee CM, Kim KY, et al. Oxidative stress and antioxidant defenses in asthmatic murine model exposed to printer emissions and environmental tobacco smoke. J Environ Pathol Toxicol Oncol. 2009;28:325–40.PubMedGoogle Scholar
  49. 49.
    Chodaczek G, Bacsi A, Dharajiya N, Sur S, Hazra TK, Boldogh I. Ragweed pollen-mediated IgE-independent release of biogenic amines from mast cells via induction of mitochondrial dysfunction. Mol Immunol. 2009;46:2505–14.PubMedCentralPubMedGoogle Scholar
  50. 50.
    Xu W, Comhair SAA, Janocha AJ, Mavrakis LA, Erzurum SC. Alteration of nitric oxide synthesis related to abnormal cellular bioenergetics in asthmatic airway epithelium. Am J Respir Crit Care Med. 2010;181:A1436.Google Scholar
  51. 51.
    Ramakrishna R, Edwards JS, McCulloch A, Palsson BO. Flux balance analysis of mitochondrial energy metabolism: consequences of systemic stoichiometric constraints. Am J Physiol Regul Integr Comp Physiol. 2001;280:R695–704.PubMedGoogle Scholar
  52. 52.
    Weller PF, Ackerman SJ, Smith JA. Eosinophil granule cationic proteins: major basic protein is distinct from the smaller subunit of eosinophil peroxidase. Leukoc Biol. 1988;43:1–4.Google Scholar
  53. 53.
    Wood LG, Gibson PG, Garg ML. Biomarkers of lipid peroxidation, airway inflammation and asthma. Eur Respir J. 2003;21:177–86.PubMedGoogle Scholar
  54. 54.
    Macmillan-Crow LA, Jahangir DL. Invited review: manganese superoxide dismutase in disease. Free Radic Res. 2001;34:325–36.PubMedGoogle Scholar
  55. 55.
    Comhair SA, Ricci KS, Arroliga M, Lara AR, Dweik RA, Song W, 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
  56. 56.
    Larsen NB, Rasmussen M, Rasmussen LJ. Nuclear and mitochondrial DNA repair: similar pathways? Mitochondrion. 2005;5:89–108.PubMedGoogle Scholar
  57. 57.
    Ames BN, Shigenaga MK, Hagen TM. Mitochondrial decay in aging. Biochim Biophys Acta. 1995;1271:165–70.PubMedGoogle Scholar
  58. 58.
    Schewe T. 15-lipoxygenase-1: a prooxidant enzyme. Biol Chem. 2002;383:365–74.PubMedGoogle Scholar
  59. 59.
    Géminard C, de Gassart A, Vidal M. Reticulocyte maturation: mitoptosis and exosome release. Biocell. 2002;26:205–15.PubMedGoogle Scholar
  60. 60.
    Chanez P, Bonnans C, Chavis C, Vachier I. 15-lipoxygenase: a Janus enzyme? Am J Respir Cell Mol Biol. 2002;27:655–8.PubMedGoogle Scholar
  61. 61.
    Andersson CK, Claesson HE, Rydell-Törmänen K, Swedmark S, Hällgren A, Erjefält JS. Mice lacking 12/15-lipoxygenase have attenuated airway allergic inflammation and remodeling. Am J Respir Cell Mol Biol. 2008;39:648–56.PubMedGoogle Scholar
  62. 62.
    Hajek AR, Lindley AR, Favoreto Jr S, Carter R, Schleimer RP, Kuperman DA. 12/15-Lipoxygenase deficiency protects mice from allergic airways inflammation and increases secretory IgA levels. J Allergy Clin Immunol. 2008;122:633–9.PubMedCentralPubMedGoogle Scholar
  63. 63.
    Ricciardolo FL. cNOS-iNOS paradigm and arginase in asthma. Trends Pharmacol Sci. 2003;24:560–1.PubMedGoogle Scholar
  64. 64.
    Mabalirajan U, Ahmad T, Leishangthem GD, Joseph DA, Dinda AK, Agrawal A, et al. Beneficial effects of high dose of L-Arginine on airway hyperresponsiveness and airway inflammation in a murine model of asthma. J Allergy Clin Immunol. 2010;125:626–35.PubMedGoogle Scholar
  65. 65.
    Shiva S, Crawford JH, Ramachandran A, Ceaser EK, Hillson T, Brookes PS, et al. Mechanisms of the interaction of nitroxyl with mitochondria. Biochem J. 2004;379:359–66.PubMedCentralPubMedGoogle Scholar
  66. 66.
    Capaldi RA. Structure and function of cytochrome oxidase. Annu Rev Biochem. 1992;59: 569–96.Google Scholar
  67. 67.
    Szabó C, Ischiropoulos H, Radi R. Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov. 2007;6:662–80.PubMedGoogle Scholar
  68. 68.
    Ahmad T, Mabalirajan U, Ghosh B, Agrawal A. Altered assymetric dimethyl arginine metabolism in bronchial epithelium of allergically inflamed lungs. Am J Resp cell Mol Biol. 2010;42:3–8.Google Scholar
  69. 69.
    Mabalirajan U, Ahmad T, Leishangthem G, Dinda AK, Agrawal A, Ghosh B. L-arginine reduces mitochondrial dysfunction and epithelial injury in murine allergic airway inflammation. Int Immunopharmacol. 2010;10:1514–9.PubMedGoogle Scholar
  70. 70.
    Scott JA, North ML, Rafii M, Huang H, Pencharz P, Subbarao P, Belik J, Grasemann H. Asymmetric dimethylarginine is increased in asthma. Am J Respir Crit Care Med. 2011;184:779–85.PubMedGoogle Scholar
  71. 71.
    Lacza Z, Pankotai E, Csordás A, Gero D, Kiss L, Horváth EM, et al. Mitochondrial NO and reactive nitrogen species production: does mtNOS exist? Nitric Oxide. 2006;14:162–8.PubMedGoogle Scholar
  72. 72.
    Sud N, Wells SM, Sharma S, Wiseman DA, Wilham J, Black SM. Asymmetric dimethylarginine inhibits HSP90 activity in pulmonary arterial endothelial cells: role of mitochondrial dysfunction. Am J Physiol Cell Physiol. 2008;294:1407–18.Google Scholar
  73. 73.
    Wells SM, Buford MC, Migliaccio CT, Holian A. Elevated asymmetric dimethylarginine alters lung function and induces collagen deposition in mice. Am J Respir Cell Mol Biol. 2009;40:179–88.PubMedCentralPubMedGoogle Scholar
  74. 74.
    Wells SM, Holian A. Asymmetric dimethylarginine induces oxidative and nitrosative stress in murine lung epithelial cells. Am J Respir Cell Mol Biol. 2007;36:520–8.PubMedCentralPubMedGoogle Scholar
  75. 75.
    Robinson NC. Functional binding of cardiolipin to cytochrome c oxidase. J Bioenerg Biomembr. 1993;25:153–63.PubMedGoogle Scholar
  76. 76.
    Ott M, Zhivotovsky B, Orrenius S. Role of cardiolipin in cytochrome c release from mitochondria. Cell Death Differ. 2007;14:1243–7.PubMedGoogle Scholar
  77. 77.
    Comhair SA, Xu W, Ghosh S, Thunnissen FB, Almasan A, Calhoun WJ, et al. Superoxide dismutase inactivation in pathophysiology of asthmatic airway remodeling and reactivity. Am J Pathol. 2005;166:663–74.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Grigoraş CC, Grigoraş A, Mihăescu T, Floarea-Stra A, Cozma L, Vereş L. Expression of the Bax proapoptotic factor in asthmatic patients. Pneumologia. 2009;58:8–12.PubMedGoogle Scholar
  79. 79.
    Kampf C, Relova AJ, Sandler S, Roomans GM. Effects of TNF-alpha, IFN-gamma and IL-beta on normal human bronchial epithelial cells. Eur Respir J. 1999;14:84–91.PubMedGoogle Scholar
  80. 80.
    Shi ZQ, Feng Y, Hou YK, Liu T, Xiu QY. A study of interferon-gamma induced airway mucous cell apoptosis and its mechanisms. Zhonghua Jie He He Hu Xi Za Zhi. 2005;28:160–3.PubMedGoogle Scholar
  81. 81.
    Chang KC, Lo CW, Fan TC, Chang MD, Shu CW, Chang CH, et al. TNF-alpha mediates eosinophil cationic protein-induced apoptosis in BEAS-2B cells. BMC Cell Biol. 2010;11:6.PubMedCentralPubMedGoogle Scholar
  82. 82.
    Serradell MC, Guasconi L, Masih DT. Involvement of a mitochondrial pathway and key role of hydrogen peroxide during eosinophil apoptosis induced by excretory-secretory products from Fasciola hepatica. Mol Biochem Parasitol. 2009;163:95–106.PubMedGoogle Scholar
  83. 83.
    Gardai SJ, Hoontrakoon R, Goddard CD, Day BJ, Chang LY, Henson PM, et al. Oxidant-mediated mitochondrial injury in eosinophil apoptosis: enhancement by glucocorticoids and inhibition by granulocyte-macrophage colony-stimulating factor. J Immunol. 2003;170: 556–66.PubMedGoogle Scholar
  84. 84.
    Dewson G, Cohen GM, Wardlaw AJ. Interleukin-5 inhibits translocation of Bax to the mitochondria, cytochrome c release, and activation of caspases in human eosinophils. Blood. 2001;98:2239–47.PubMedGoogle Scholar
  85. 85.
    Druilhe A, Létuvé S, Pretolani M. Glucocorticoid-induced apoptosis in human eosinophils: mechanisms of action. Apoptosis. 2003;8:481–95.PubMedGoogle Scholar
  86. 86.
    Walsh GM, Sexton DW, Blaylock MG. Corticosteroids, eosinophils and bronchial epithelial cells: new insights into the resolution of inflammation in asthma. J Endocrinol. 2003;178(1): 37–43.PubMedGoogle Scholar
  87. 87.
    Cruz AA, Bousquet PJ. The unbearable cost of severe asthma in underprivileged populations. Allergy. 2009;64(3):319–21.PubMedGoogle Scholar
  88. 88.
    Holgate ST, Lackie P, Wilson S, Roche W, Davies D. Bronchial epithelium as a key regulator of airway allergen sensitization and remodeling in asthma. Am J Respir Crit Care Med. 2000;162:S113–7.PubMedGoogle Scholar
  89. 89.
    O’Sullivan MP, Tyner JW, Holtzman MJ. Apoptosis in the airways: another balancing act in the epithelial program. Am J Respir Cell Mol Biol. 2003;29:3–7.PubMedGoogle Scholar
  90. 90.
    Holgate ST. The inflammation-repair cycle in asthma: the pivotal role of the airway epithelium. Clin Exp Allergy. 1998;28 Suppl 5:97–103.PubMedGoogle Scholar
  91. 91.
    Holgate ST, Holloway J, Wilson S, Bucchieri F, Puddicombe S, Davies DE. Epithelial-mesenchymal communication in the pathogenesis of chronic asthma. Proc Am Thorac Soc. 2004;1:93–8.PubMedGoogle Scholar
  92. 92.
    Davies DE, Holgate ST. Asthma: the importance of epithelial mesenchymal communication in pathogenesis. Inflammation and the airway epithelium in asthma. Int J Biochem Cell Biol. 2002;34:1520–6.PubMedGoogle Scholar
  93. 93.
    Zimmermann N, King NE, Laporte J, Yang M, Mishra A, Pope SM, et al. Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis. J Clin Invest. 2003;111:1863–74.PubMedCentralPubMedGoogle Scholar
  94. 94.
    Delwing D, Delwing D, Chiarani F, Kurek AG, Wyse AT. Proline reduces brain cytochrome c oxidase: prevention by antioxidants. Int J Dev Neurosci. 2007;25:17–22.PubMedGoogle Scholar
  95. 95.
    Trian T, Benard G, Begueret H, Rossignol R, Girodet PO, Ghosh D, et al. Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma. J Exp Med. 2007;204:3173–81.PubMedCentralPubMedGoogle Scholar
  96. 96.
    Lee I, Salomon AR, Ficarro S, Mathes I, Lottspeich F, Grossman LI, et al. cAMP-dependent tyrosine phosphorylation of subunit I inhibits cytochrome c oxidase activity. J Biol Chem. 2005;280:6094–100.PubMedGoogle Scholar
  97. 97.
    Pelaia G, Di Paola ED, De Sarro G, Marsico SA. Is the mitochondrial benzodiazepine receptor involved in the control of airway smooth muscle tone? Gen Pharmacol. 1997;28:495–8.PubMedGoogle Scholar
  98. 98.
    Ten Broeke R, Blalock JE, Nijkamp FP, Folkerts G. Calcium sensors as new therapeutic targets for asthma and chronic obstructive pulmonary disease. Clin Exp Allergy. 2004;34: 170–6.PubMedGoogle Scholar
  99. 99.
    Duchen MR. Contributions of mitochondria to animal physiology: from homeostatic sensor to calcium signalling and cell death. J Physiol. 1999;516:1–17.PubMedCentralPubMedGoogle Scholar
  100. 100.
    Herrington J, Park YB, Babcock DF, Hille B. Dominant role of mitochondria in clearance of large Ca2+ loads from rat adrenal chromaffin cells. Neuron. 1996;16:219–28.PubMedGoogle Scholar
  101. 101.
    Peng TI, Jou MJ. Oxidative stress caused by mitochondrial calcium overload. Ann N Y Acad Sci. 2010;1201:183–8.PubMedGoogle Scholar
  102. 102.
    Feissner RF, Skalska J, Gaum WE, Sheu SS. Crosstalk signaling between mitochondrial Ca2+ and ROS. Front Biosci. 2009;14:1197–218.Google Scholar
  103. 103.
    Cantero-Recasens G, Fandos C, Rubio-Moscardo F, Valverde MA, Vicente R. The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Hum Mol Genet. 2010;19:111–21.PubMedGoogle Scholar
  104. 104.
    Folkerts G, Busse WW, Nijkamp FP, Sorkness R, Gern JE. Virus induced airway hyperresponsiveness and asthma. Am J Respir Crit Care Med. 1998;157:1708–20.PubMedGoogle Scholar
  105. 105.
    You D, Becnel D, Wang K, Ripple M, Daly M, Cormier SA. Exposure of neonates to respiratory syncytial virus is critical in determining subsequent airway response in adults. Respir Res. 2006;7:107.PubMedCentralPubMedGoogle Scholar
  106. 106.
    Punyadarsaniya D, Liang CH, Winter C, Petersen H, Rautenschlein S, Hennig-Pauka I, et al. Infection of differentiated porcine airway epithelial cells by influenza virus: differential susceptibility to infection by porcine and avian viruses. PLoS One. 2011;6:e28429.PubMedCentralPubMedGoogle Scholar
  107. 107.
    Seth RB, Sun L, Ea CK, Chen ZJ. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell. 2005;122:669–82.PubMedGoogle Scholar
  108. 108.
    Qi B, Huang Y, Rowe D, Halliday G. VISA–a pass to innate immunity. Int J Biochem Cell Biol. 2007;39:287–91.PubMedGoogle Scholar
  109. 109.
    Tang ED, Wang CY. MAVS self-association mediates antiviral innate immune signaling. J Virol. 2009;83:3420–8.PubMedCentralPubMedGoogle Scholar
  110. 110.
    Seth RB, Sun L, Chen ZJ. Antiviral innate immunity pathways. Cell Res. 2006;16:141–7.PubMedGoogle Scholar
  111. 111.
    Rehwinkel J, Reis e Sousa C. RIGorous detection: exposing virus through RNA sensing. Science. 2010;327:284–6.PubMedGoogle Scholar
  112. 112.
    Land JM, Morgan-Hughes JA, Hargreaves I, Heales SJ. Mitochondrial disease: a historical, biochemical, and London perspective. Neurochem Res. 2004;29:483–91.PubMedGoogle Scholar
  113. 113.
    Szeto HH. Mitochondria-targeted peptide antioxidants: novel neuroprotective agents. AAPS J. 2006;8:521–31.Google Scholar
  114. 114.
    Armstrong JS. Mitochondrial medicine: pharmacological targeting of mitochondria in disease. Br J Pharmacol. 2007;151:1154–65.PubMedCentralPubMedGoogle Scholar
  115. 115.
    Szewczyk A, Wojtczak L. Mitochondria as a pharmacological target. Pharmacol Rev. 2002;54:101–27.PubMedGoogle Scholar
  116. 116.
    Barnhill AE, Brewer MT, Carlson SA. Adverse effects of antimicrobials via predictable or idiosyncratic inhibition of host mitochondrial components. Antimicrob Agents Chemother. 2012;56:4046–51.PubMedCentralPubMedGoogle Scholar
  117. 117.
    Islam MN, Das SR, Emin MT, Wei M, Sun L, Westphalen K, et al. Mitochondrial transfer from bone-marrow derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med. 2012;18:759–65.PubMedCentralPubMedGoogle Scholar
  118. 118.
    Jones CP, Rankin SM. Bone marrow-derived stem cells and respiratory disease. Chest. 2011;140:205–11.PubMedGoogle Scholar
  119. 119.
    Kapoor S, Patel SA, Kartan S, Axelrod D, Capitle E, Rameshwar P. Tolerance-like mediated suppression by mesenchymal stem cells in patients with dust mite allergy-induced asthma. J Allergy Clin Immunol. 2012;129:1094–101.PubMedGoogle Scholar
  120. 120.
    Mabalirajan U, Dinda AK, Sharma SK, Ghosh B. Esculetin restores mitochondrial dysfunction and reduces allergic asthma features in experimental murine model. J Immunol. 2009;183:2059–67.PubMedGoogle Scholar
  121. 121.
    Mabalirajan U, Aich J, Sharma SK, Ghosh B. Effects of vitamin E on mitochondrial dysfunction and asthma features in an experimental allergic murine model. J Appl Physiol. 2009;107:1285–92.PubMedCentralPubMedGoogle Scholar
  122. 122.
    Ahmad T, Mabalirajan U, Sharma A, Ghosh B, Agrawal A. Simvastatin improves epithelial dysfunction and airway hyperresponsiveness: from ADMA to asthma. Am J Resp Cell Mol Biol. 2011;44:531–9.Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Ulaganathan Mabalirajan
    • 1
  • Anurag Agrawal
    • 1
  • Balaram Ghosh
    • 2
    Email author
  1. 1.Molecular Immunogenetics Laboratory, Centre of Excellence for Translational Research in Asthma and Lung DiseaseCSIR- Institute of Genomics and Integrative BiologyDelhiIndia
  2. 2.Molecular Immunogenetics LaboratoryCSIR- Institute of Genomics and Integrative Biology, Delhi University Campus (North)DelhiIndia

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