Figure 5.

Schematic of proposed processes upon mitochondrial DNA (mtDNA) depletion in lung epithelial cells. During homeostasis, ATP is produced by oxidative phosphorylation and there is a balance between active and inactive PI3K/GSK-3βsignaling, ensuring limited glycolysis. Upon mitochondrial damage/dysfunction induced by mtDNA depletion, increased release of reactive oxygen species (ROS) production results in increased activity of redox sensitive kinases such as PI3K and a subsequent increase in production of pro-inflammatory mediators. Cells can no longer perform normal electron transport for ATP synthesis and rely on ATP derived from glycolysis, which is accompanied by impairment/exhaustion of repair responses. This glycolytic switch is promoted by the activation of PI3K signaling and subsequent inactivation of GSK-3β and HDAC2, resulting in reduced corticosteroid sensitivity of pro-inflammatory responses as well as reduced potential of corticosteroids to improve barrier integrity, the latter through mechanisms that need further elucidation.