Endoplasmic reticulum-mitochondrial crosstalk in the development of idiopathic pulmonary fibrosis

Idiopathic Pulmonary Fibrosis (IPF) has a remarkable age-related onset and hence, several age-related factors/stress mechanisms play a major role in triggering the pathological events. It is well-identified that under certain settings including hypoxia, oxidative stress or altered calcium levels, unfolded or misfolded proteins accumulate in the endoplasmic reticulum (ER) that lead to a disrupted ER homeostasis and its crosstalk with the mitochondria. The discrete roles of ER stress and dysfunctional mitochondria in the alveolar epithelium have been implicated in the pathogenesis of IPF, but the putative pathomechanistic role of a disturbance of this intracellular organelle interplay in driving AECII apoptosis and thereby lung fibrosis still remains elusive. In the current study, we aimed to understand this crosstalk by studying the ER-mitochondrial interface in IPF and in relevant in vivo and in vitro models. We identified by immunohistological analysis that the alveolar epithelial cells type II (AECII) of IPF patients show enhanced positivity for several mitochondrial associated membrane (MAM) proteins including sigma-1R, IP₃R3 and PACS-2. In mouse lung epithelial cells with induced overexpression of the terminal ER stress marker, C/EBP homologous protein (CHOP), we observed altered mitochondria as well as a significant increase in the PACS-2 protein levels. These preliminary data hint towards a dysregulated interaction between ER and mitochondria in IPF and a detailed understanding of the disturbances may result in novel treatment modalities, resulting in reduced epithelial apoptosis and lung fibrosis.