Role of Lysocardiolipin AcylTransferase in Lung Epithelial Cell Apoptosis
thesisposted on 27.11.2018 by Mounica Bandela
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Chronic Obstructive Pulmonary Disorder (COPD), primarily caused by cigarette smoke (CS), is a leading cause of mortality in the US, and it is preventable by stopping smoking. CS-induced oxidative damage of lungs results in mitochondrial dysfunction. Cardiolipin (CL), which is predominantly localized in the inner mitochondrial membrane plays an important role in mitochondrial function and the C18:2 fatty acid of profile of CL in mitochondria is regulated by lysocardiolipin acyltransferase (LYCAT) that is also predominantly localized in the mitochondria. Not much is known on LYCAT and its role in CS-induced apoptosis in lung epithelium. In the present study we investigated the role of LYCAT, in the pathogenesis of COPD. CS enhanced mRNA and protein expression of LYCAT in lung bronchial epithelial cells, and inhibition of LYCAT with a newly developed peptide inhibitor attenuated CS-induced lung epithelial cell apoptosis. Exposure of lung epithelial cells to CS increased total and mitochondrial ROS generation and blocking LYCAT with the inhibitor reduced total and mitochondrial ROS. A 3D homology model for LYCAT was developed using computer-assisted technology to identify potential sites to inhibit the activity of LYCAT. A template structure 1BD2 was retrieved from PDB-BLAST to build the homology model, which was validated for structural assessment using Ramachandran plot, QMEAN and Z-scores. Using this approach, ~84.76% of residues were in favored region of the Ramachandran plot. The active site of the model was determined using CASTp with 1417.854 Å3 and 2029.864 Å2 as the surface area and volume respectively. The validated homology model was docked with the peptide inhibitor using HPEPDOCK which gave multiple models, among those the one with lowest docking energy i.e., -251.093 Kcalmol-1 was considered as best binding model. Thus, LYCAT was identified as a potential target in COPD and there is need to develop novel small molecule inhibitors.