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Mitochondrial Structural Changes and Dysfunction Are Associated with Experimental Allergic Asthma¹

Ulaganathan Mabalirajan^*,, Amit Kumar Dinda, Sarvesh Kumar^*, Reema Roshan^*, Pooja Gupta^*, Surendra Kumar Sharma and Balaram Ghosh^2,*

^* Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative Biology, Delhi, India; and Division of Renal Pathology, Department of Pathology, and Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India

An imbalance between Th1 and Th2 immune response is crucial for the development of pathophysiological features of asthma. A Th2-dominant response produces oxidative stress in the airways, and it is thought to be one of the crucial components of asthma pathogenesis. Although mitochondrion is a crucial organelle to produce endogenous reactive oxygen species, its involvement in this process remains unexplored as yet. We demonstrate in this study that OVA-induced experimental allergic asthma in BALB/c mice is associated with mitochondrial dysfunction, such as reduction of cytochrome c oxidase activity in lung mitochondria, reduction in the expression of subunit III of cytochrome c oxidase in bronchial epithelium, appearance of cytochrome c in the lung cytosol, decreased lung ATP levels, reduction in the expression of 17 kDa of complex I in bronchial epithelium, and mitochondrial ultrastructural changes such as loss of cristae and swelling. However, there was no change in the expression of subunits II and III of cytochrome c oxidase. Interestingly, administration of IL-4 mAb reversed these mitochondrial dysfunction and structural changes. In contrast, IFN- mAb administration neither reversed nor further deteriorated the mitochondrial dysfunction and structural changes compared with control asthmatic mice administered with isotypic control Ab, although airway hyperresponsiveness deteriorated further. These results suggest that mitochondrial structural changes and dysfunction are associated with allergic asthma. These findings may help in the development of novel drug molecules targeting mitochondria for the treatment of asthma.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Net Work Project (NWP0033) of Council of Scientific and Industrial Research (Government of India) and Task Force Project SMM0006 of Council of Scientific and Industrial Research (Government of India). U.M. was supported by a fellowship from the Indian Council of Medical Research.

² Address correspondence and reprint requests to Dr. Balaram Ghosh, Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative Biology, Mall Road, Delhi-110007. E-mail address: bghosh{at}igib.res.in

³ Abbreviations used in this paper: AHR, airway hyperresponsiveness; A.CON, asthmatic control; BAL, bronchoalveolar lavage; COX_ETC, cytochrome c oxidase of electron transport chain; CYTO, cytosolic fraction; DCP, double-chamber plethysmography; DEX, dexamethasone; HODE, hydroxyoctadecaenoic acid; IHC, immunohistochemistry; L-OOH, lipid hydroperoxide; MCh, methacholine; N.CON, normal control; Penh, enhanced pause; SCP, single-chamber plethysmography; sGaw, specific airway conductance; sRaw, specific airway resistance; ISO, isotypic.

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