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.
