Mitochondrial iron regulates AEC2 dysfunction, senescence and senescent associated secretory phenotype in response to bleomycin challenge.

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a form of interstitial lung disease (ILD), which is characterized by progressive dyspnoea and a decline in lung function. The exact cause of IPF is unknown, however, accumulating evidence highlights a role for mitochondria in alveolar type II epithelial cells (AEC2) dysfunction in the pathogenesis of IPF. In conjunction with this, iron has also been suggested to play a role in the development of the disease, with recent studies showing alterations of iron levels in the lungs of individuals with IPF. However, the role of mitochondrial iron transporters, Mitoferrin 1 (Mfrn1) and Mitoferrin 2 (Mfrn2) play in AEC2 function and disease progression remains unknown. Here, we show that the loss of Mfrn1 and Mfrn2 leads to a dysfunctional senescent phenotype, which is augmented upon bleomycin treatment. We show that by depleting Mfrn1 and Mfrn2 in AEC2 cells, intracellular iron levels decrease both in vitro and in vivo. These reduced intracellular iron levels associate with AEC2 cell dysfunction and altered expression levels of cell senescence markers after bleomycin treatment. We suggest a crucial role for iron dyshomeostasis in the development of dysfunctional AEC2 cells in bleomycin-induced fibrosis in vitro and in vivo. Furthermore, we propose that senescent AEC2 secrete an iron-related “senescent associated secretory phenotype” (SASP) which primes a profibrotic, inflammatory microenvironment.