Autophagy Reprograms Alveolar Progenitor Cell Metabolism in Response to Lung Injury

Abstract

Summary: Autophagy is a protective cellular mechanism in response to stress conditions. However, whether autophagy is required for maintenance of the alveolar epithelium is unknown. Here, we report that the loss of autophagy-related 5 (Atg5) in AT2 cells worsened bleomycin-induced lung injury. Mechanistically, during bleomycin injury, autophagy downregulated lipid metabolism but upregulated glucose metabolism in AT2 cells for alveolar repair. Chemical blockade of fatty acid synthesis promoted organoid growth of AT2 cells and counteracted the effects of autophagy loss on bleomycin injury. However, genetic loss of glucose transporter 1, interference with glycolysis, or interference with the pentose phosphate pathway reduced the proliferation of AT2 cells. Inhibition of glucose metabolism exacerbated the effects of bleomycin injury. Failure of autophagy generated additional hydrogen peroxide, which reduced AT2 cell proliferation. These data highlight an essential role for autophagy in reprogramming the metabolism of alveolar progenitor cells to meet energy needs for alveolar epithelial regeneration. : Metabolic reprogramming in stem/progenitor cells is essential for tissue maintenance and regeneration after injuries. In this article, Chen and colleagues report that autophagy protects from bleomycin-induced lung injury by switching lipid metabolism to glucose metabolism in AT2 progenitor cells. Repairing capacity of AT2 cells is positively regulated by glucose metabolism, but negatively controlled by lipid metabolism. Keywords: autophagy, AT2 progenitor cells, lung injury, glucose metabolism, lipid metabolism, oxidative stress, metabolic reprogramming, organoids