DRP1-Mediated Mitochondrial Fission Regulates the Lung Epithelial Response to Allergen

Abstract

Background: Mitochondria regulate a myriad of cellular needs and functions. Dysregulation of mitochondrial control within airway epithelial cells has been implicated in the pro-inflammatory response to allergens in asthmatics. Because of their multifaceted nature, mitochondrial structure needs to be tightly regulated through fission and fusion. Dynamin Related Protein 1 (DRP1), a cytosolic GTPase, is a key driver of mitochondrial fission. During allergic asthma, airway epithelial mitochondria appear smaller and structurally altered. The role of DRP1-mediated mitochondrial fission, however, has not been fully elucidated in allergic airway disease. Methods: We used a Human Bronchial Epithelial Cell line (HBECs), primary Mouse Tracheal Epithelial Cells (MTECs), and conditional ablation of DRP1 in lung epithelial cells to investigate mitochondrial fission and its impact on the pro-inflammatory response to House Dust Mite (HDM) in vitro and in vivo. Results: Our data suggest that, following HDM challenge, mitochondrial fission is rapidly upregulated in airway epithelial cells and precedes production of pro-inflammatory cytokines and chemokines. Further, deletion of DRP1 in lung epithelial cells lead to decreased mitochondrial fission and enhanced pro-inflammatory signaling in response to HDM. Analysis of lung epithelial specific DRP1 deletion in mice demonstrated enhanced Airway Hyper Responsiveness (AHR), inflammation, differential mucin transcription, and epithelial cell death. Conclusions: Mitochondrial fission is rapidly upregulated in airway epithelial cells following HDM exposure, prior to epithelial release of pro-inflammatory cytokines and chemokines. Deletion of DRP1, a necessary pro- fission protein, reduces fission and enhances the pro-inflammatory epithelial response to HDM, exacerbating the allergic response.

The relationship between cholesterol metabolism and mitochondrial function in chronic obstructive pulmonary diseases

“…A similar phenomenon was observed in the airway epithelium stimulated by PM2.5, accompanied by a decrease in mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis 55 . In house dust mite‐induced asthma, downregulation of mitochondrial fission by knockdown of DRP1 increased the inflammatory response and cell death, and aggravated airway mucus hypersecretion and airway hyperresponsiveness 56 . These results indicated that DRP1 had different effects on inflammation due to different stimuli of pathological processes in the lung.…”

“…55 In house dust mite-induced asthma, downregulation of mitochondrial fission by knockdown of DRP1 increased the inflammatory response and cell death, and aggravated airway mucus hypersecretion and airway hyperresponsiveness. 56 These results indicated that DRP1 had different effects on inflammation due to different stimuli of pathological processes in the lung.…”