Patel, Avignat S.Song, Jin WooChu, SarahMizumura, KenjiOsorio, Juan C.Shi, YingEl-Chemaly, SouheilLee, Chun GeunRosas, IvanElias, Jack A.Choi, Augustine M. K.Morse, Danielle2015-04-012015Patel, A. S., J. W. Song, S. G. Chu, K. Mizumura, J. C. Osorio, Y. Shi, S. El-Chemaly, et al. 2015. “Epithelial Cell Mitochondrial Dysfunction and PINK1 Are Induced by Transforming Growth Factor- Beta1 in Pulmonary Fibrosis.” PLoS ONE 10 (3): e0121246. doi:10.1371/journal.pone.0121246. http://dx.doi.org/10.1371/journal.pone.0121246.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:14351320Background: Epithelial cell death is a major contributor to fibrogenesis in the lung. In this study, we sought to determine the function of mitochondria and their clearance (mitophagy) in alveolar epithelial cell death and fibrosis. Methods: We studied markers of mitochondrial injury and the mitophagy marker, PTEN-induced putative kinase 1 (PINK1), in IPF lung tissues by Western blotting, transmission electron microscopy (TEM), and immunofluorescence. In vitro experiments were carried out in lung epithelial cells stimulated with transforming growth factor-β1 (TGF-β1). Changes in cell function were measured by Western blotting, flow cytometry and immunofluorescence. In vivo experiments were performed using the murine bleomycin model of lung fibrosis. Results: Evaluation of IPF lung tissue demonstrated increased PINK1 expression by Western blotting and immunofluorescence and increased numbers of damaged mitochondria by TEM. In lung epithelial cells, TGF-β1 induced mitochondrial depolarization, mitochondrial ROS, and PINK1 expression; all were abrogated by mitochondrial ROS scavenging. Finally, Pink1-/- mice were more susceptible than control mice to bleomycin induced lung fibrosis. Conclusion: TGF-β1 induces lung epithelial cell mitochondrial ROS and depolarization and stabilizes the key mitophagy initiating protein, PINK1. PINK1 ameliorates epithelial cell death and may be necessary to limit fibrogenesis.en-USJournal Article2015-04-0110.1371/journal.pone.0121246