Loss of ANT1 Increases Fibrosis and Epithelial Cell Senescence in Idiopathic Pulmonary Fibrosis

Am J Respir Cell Mol Biol. 2023 Jul 24. doi: 10.1165/rcmb.2022-0315OC. Online ahead of print.ABSTRACTIdiopathic Pulmonary Fibrosis (IPF) is an interstitial lung disease characterized by progressive lung scarring and remodeling. Although treatments exist that slow disease progression, IPF is irreversible and there is no cure. Cellular senescence, a major hallmark of aging, has been implicated in IPF pathogenesis, and mitochondrial dysfunction is increasingly recognized as a driver of senescence. Adenine nucleotide translocases (ANTs) are abundant mitochondrial ATP-ADP transporters critical for regulating cell fate and maintaining mitochondrial function. We sought to determine how alterations in ANTs influence cellular senescence in pulmonary fibrosis. We found SLC25A4 (ANT1) and SLC25A5 (ANT2) expression is reduced in the lungs of IPF patients and particularly within alveolar type II (AT2) cells by single cell RNA sequencing and tissue staining. Loss of ANT1 by siRNA in lung epithelial cells resulted in increased senescence markers such as beta-galactosidase and p21 with a reduction in the NAD+/NADH ratio. Bleomycin-treated ANT1 knockdown cells also had increased senescence markers compared to bleomycin-treated control cells. Loss of ANT1 in AT2 cells resulted in a reduction in alveolar organoid growth with an increase in p21 by staining. Global loss of ANT1 resulted in worse lung fibrosis and increased senescence in the bleomycin and asbestos-induced mouse models of pulmonary...
Source: Am J Respir Cell Mol... - Category: Respiratory Medicine Authors: Source Type: research