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The early asthmatic response is associated with glycolysis, calcium binding and mitochondria activity as revealed by proteomic analysis in rats
The differential role of mitochondria in asthmatic lung
Ulaganathan Mabalirajan, Institute of Genomics and Integrative Biology, Mallroad, Delhi, India
7 September 2010
This study revealed novel and interesting findings, such as glycolysis and calcium binding in asthmatic early airway response (EAR) in murine OVA model. In addition, they found increased biological activity of mitochondria in asthmatic mice lung during EAR. However, we think that interpretation and discussion related to the mitochondria needs some caution, update and a holistic view. Asthma is a heterogeneous disease and various immune cells and structural cells participate in its pathophysiology. Recent literature has highlighted the importance of mitochondria in asthma pathogenesis. A common finding in asthma is epithelial injury and apoptosis associated with high levels of oxo-nitrosative stress. Mitochondrial dysfunction contributes importantly to this process, leading to large production of reactive oxygen species (ROS), which in the presence of disordered nitric oxide metabolism further leads to generation of reactive nitrogen species. It has been shown that coenzyme Q and vitamin E which are mitochondrial target antioxidants and esculetin have beneficial effects in asthma with reduction in mitochondrial dysfunction [1-3]. Due to the heterogeneous nature of asthma, multifunctionality of mitochondria and cell-lineage specific effects, the exact role of mitochondria in asthma pathogenesis is not clear. Current literature revealed that mitochondria seem to have differential roles in asthmatic lungs. Increased glycolysis may accompany reduced mitochondrial electron chain activity in the context of hypoxic response activation by hypoxia inducible factor-1 [5]. This preserves the integrity of the electron transfer chain during conditions of increased electron accumulation and ROS generation from complex III. Interestingly, such hypoxic response can be triggered by fall in available oxygen to complex IV as well as any other factor(s) that increased ROS generation. It is noteworthy that mitochondrial ROS increase the secretion of proinflammatory mediators such as histamine and serotonin from mast cell to initiate EAR [6]. In addition, it seems that mitochondrial dysfunction activates adoptive immune response by inducing IL-4 production [6]. In this context, we found that neutralizing IL-4 ameliorated the mitochondrial dysfunction along with the restoration of mitochondrial ultrastructural changes in bronchial epithelia [7] in OVA murine model of asthma. In support of this view, underlying mitochondrial dysfunction in airway epithelium of ragweed allergen sensitized mice aggravated the features of asthma such as bronchial hyperresponsiveness [8]. In contrast to these findings of mitochondrial dysfunction in mast cells and bronchial epithelia, increased mitochondrial activity and mitochondrial biogenesis have been observed in asthmatic airway smooth muscle and it has been suggested that these are crucial in smooth muscle hypertrophy of airway remodeling [9]. In addition, modulation of mitochondrial function may delay apoptosis of immune cells such as eosinophils and neutrophils [10]. In summary, mitochondrial function seems to be differentially altered in different cell types of asthmatic lungs and this may vary depending on the natural evolution of asthma pathology. Therefore, careful investigations are required to dissect the exact role of mitochondria in cell specific manner for asthma pathogenesis.
Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma & Lung disease, Institute of Genomics and Integrative Biology, India (UM, AA and BG), and Department of Pathology, All India Institute of Medical Sciences, India (AKD).
References
1. Gvozdjáková A, Kucharská J, Bartkovjaková M, Gazdíková K, Gazdík FE: Coenzyme Q10 supplementation reduces corticosteroids dosage in patients with bronchial asthma. Biofactors 2005, 25:235-240. 2. 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: 2059-2067. 3. 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, 107:1285-1292. 4. Xu YD, Cui JM, Wang Y, Yin LM, Gao CK, Liu YY, Yang YQ: The early asthmatic response is associated with glycolysis, calcium binding and mitochondria activity as revealed by proteomic analysis in rats. Respir Res 2010, 11:107. 5. Semenza GL: Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology (Bethesda) 2004, 19:176-82. 6. 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, 46:2505-2514. 7. 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: 3540-3548. 8. Aguilera-Aguirre L, Bacsi A, Saavedra-Molina A, Kurosky A, Sur S, Boldogh I: Mitochondrial dysfunction increases allergic airway inflammation. J Immunol 2009, 183:5379-5387. 9. Trian T, Benard G, Begueret H, Rossignol R, Girodet PO, Ghosh D, Ousova O, Vernejoux JM, Marthan R, Tunon-de-Lara JM, Berger P: Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma. J Exp Med 2007, 204:3173-3181. 10. 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, 98:2239-2247.
The differential role of mitochondria in asthmatic lung
7 September 2010
This study revealed novel and interesting findings, such as glycolysis and calcium binding in asthmatic early airway response (EAR) in murine OVA model. In addition, they found increased biological activity of mitochondria in asthmatic mice lung during EAR. However, we think that interpretation and discussion related to the mitochondria needs some caution, update and a holistic view.
Asthma is a heterogeneous disease and various immune cells and structural cells participate in its pathophysiology. Recent literature has highlighted the importance of mitochondria in asthma pathogenesis. A common finding in asthma is epithelial injury and apoptosis associated with high levels of oxo-nitrosative stress. Mitochondrial dysfunction contributes importantly to this process, leading to large production of reactive oxygen species (ROS), which in the presence of disordered nitric oxide metabolism further leads to generation of reactive nitrogen species. It has been shown that coenzyme Q and vitamin E which are mitochondrial target antioxidants and esculetin have beneficial effects in asthma with reduction in mitochondrial dysfunction [1-3]. Due to the heterogeneous nature of asthma, multifunctionality of mitochondria and cell-lineage specific effects, the exact role of mitochondria in asthma pathogenesis is not clear. Current literature revealed that mitochondria seem to have differential roles in asthmatic lungs.
Increased glycolysis may accompany reduced mitochondrial electron chain activity in the context of hypoxic response activation by hypoxia inducible factor-1 [5]. This preserves the integrity of the electron transfer chain during conditions of increased electron accumulation and ROS generation from complex III. Interestingly, such hypoxic response can be triggered by fall in available oxygen to complex IV as well as any other factor(s) that increased ROS generation. It is noteworthy that mitochondrial ROS increase the secretion of proinflammatory mediators such as histamine and serotonin from mast cell to initiate EAR [6]. In addition, it seems that mitochondrial dysfunction activates adoptive immune response by inducing IL-4 production [6]. In this context, we found that neutralizing IL-4 ameliorated the mitochondrial dysfunction along with the restoration of mitochondrial ultrastructural changes in bronchial epithelia [7] in OVA murine model of asthma. In support of this view, underlying mitochondrial dysfunction in airway epithelium of ragweed allergen sensitized mice aggravated the features of asthma such as bronchial hyperresponsiveness [8]. In contrast to these findings of mitochondrial dysfunction in mast cells and bronchial epithelia, increased mitochondrial activity and mitochondrial biogenesis have been observed in asthmatic airway smooth muscle and it has been suggested that these are crucial in smooth muscle hypertrophy of airway remodeling [9]. In addition, modulation of mitochondrial function may delay apoptosis of immune cells such as eosinophils and neutrophils [10].
In summary, mitochondrial function seems to be differentially altered in different cell types of asthmatic lungs and this may vary depending on the natural evolution of asthma pathology. Therefore, careful investigations are required to dissect the exact role of mitochondria in cell specific manner for asthma pathogenesis.
Sincerely,
Ulaganathan Mabalirajan MBBS, PhD
Amit Kumar Dinda, MD, PhD
Anurag Agrawal MD, PhD
Balaram Ghosh PhD, FNASc, FASc
Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma & Lung disease, Institute of Genomics and Integrative Biology, India (UM, AA and BG), and Department of Pathology, All India Institute of Medical Sciences, India (AKD).
References
1. Gvozdjáková A, Kucharská J, Bartkovjaková M, Gazdíková K, Gazdík FE: Coenzyme Q10 supplementation reduces corticosteroids dosage in patients with bronchial asthma. Biofactors 2005, 25:235-240.
2. 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: 2059-2067.
3. 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, 107:1285-1292.
4. Xu YD, Cui JM, Wang Y, Yin LM, Gao CK, Liu YY, Yang YQ: The early asthmatic response is associated with glycolysis, calcium binding and mitochondria activity as revealed by proteomic analysis in rats. Respir Res 2010, 11:107.
5. Semenza GL: Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology (Bethesda) 2004, 19:176-82.
6. 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, 46:2505-2514.
7. 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: 3540-3548.
8. Aguilera-Aguirre L, Bacsi A, Saavedra-Molina A, Kurosky A, Sur S, Boldogh I: Mitochondrial dysfunction increases allergic airway inflammation. J Immunol 2009, 183:5379-5387.
9. Trian T, Benard G, Begueret H, Rossignol R, Girodet PO, Ghosh D, Ousova O, Vernejoux JM, Marthan R, Tunon-de-Lara JM, Berger P: Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma. J Exp Med 2007, 204:3173-3181.
10. 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, 98:2239-2247.
Competing interests
None