Metabolic modulators augment cell proliferation in ANT2 metabolically deficient human bronchial epithelium cells

Summary: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibrosis and remodeling in the lung tissue with current treatments only slowing disease progression. Cellular senescence of epithelial cells has been implicated in IPF pathogenesis. Mitochondrial dysfunction has been linked to senescence however, the underlying mechanism remains unknown. Adenine nucleotide translocases (ANTS) are abundant ATP-ADP transporters central to mitochondrial integrity and bioenergetic metabolism. Previously, our lab found reduced ANT2 expression in IPF patient lungs and ANT2 loss reduces cell proliferation. In this study, we explored if metabolically relevant compounds could restore transcriptional & functional changes to those in normal human bronchial epithelium. Utilizing gene expression data from normal and ANT2 knockout cells, we applied an ML algorithm to identify compounds based on gene/pathway alterations. Focusing on 4 drugs of interest, we identified several compounds from the ALOX12/ALOX15 pathways and carnitine transport that augmented cell proliferation. Further studies will measure senescent markers and utilize primary alveolar organoids as proof of therapeutic potential. Satoshi Okawa and Corrine R. Kliment