[HTML][HTML] Epithelial cell mitochondrial dysfunction and PINK1 are induced by transforming growth factor-beta1 in pulmonary fibrosis
AS Patel, JW Song, SG Chu, K Mizumura, JC Osorio… - PloS one, 2015 - journals.plos.org
AS Patel, JW Song, SG Chu, K Mizumura, JC Osorio, Y Shi, S El-Chemaly, CG Lee…
PloS one, 2015•journals.plos.orgBackground 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 …
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 …
Background
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.
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