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

Sierra R Bruno,Vikas Anathy,Amit Kumar,Zoe F Mark,Ravishankar Chandrasekaran,Anne E Dixon,Brian Cunniff,Bethany Mihavics,Joseph Walzer,Jonathon Cahoon,Nicolas Chamberlain,Emily Nakada

doi:10.3390/ijms222011125

Sierra R Bruno, Vikas Anathy + Show 10 more

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https://doi.org/10.3390/ijms222011125

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Abstract

Mitochondria regulate a myriad of cellular functions. Dysregulation of mitochondrial control within airway epithelial cells has been implicated in the pro-inflammatory response to allergens in asthma patients. Because of their multifaceted nature, mitochondrial structure must be tightly regulated through fission and fusion. Dynamin Related Protein 1 (DRP1) 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 epithelial response to allergens. We used a Human Bronchial Epithelial Cell line (HBECs), primary Mouse Tracheal Epithelial Cells (MTECs), and conditional DRP1 ablation in lung epithelial cells to investigate the impact of mitochondrial fission on the pro-inflammatory response to house dust mite (HDM) in vitro and in vivo. 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 leads to decreased fission and enhanced pro-inflammatory signaling in response to HDM in vitro, as well as enhanced airway hyper-responsiveness (AHR), inflammation, differential mucin transcription, and epithelial cell death in vivo. Mitochondrial fission, therefore, regulates the lung epithelial pro-inflammatory response to HDM.

Highlights

Asthma is an inflammatory respiratory disease that is estimated to affect over 339 million people globally [1]
The expression of two transcript variants of Dynamin Related Protein 1 (DRP1), both expressed in most human cell types, is modestly but significantly upregulated in severe asthmatic bronchial epithelial cells compared to non-asthmatic controls (Figure S1), indicating a potential role for DRP1 in regulation of asthma progression
We found that house dust mite (HDM) exposure of human bronchial epithelial cells (HBEs) acutely increased the phosphorylation of DRP1 at Serine 616 (S616) at 40 min post-HDM exposure, and this phosphorylation dissipated within 120 min from HDM exposure (Figure 1B,C)

Summary

Introduction

Asthma is an inflammatory respiratory disease that is estimated to affect over 339 million people globally [1]. Recent studies have demonstrated that allergen-induced alterations in mitochondrial function drives epithelial pro-inflammatory signaling, apoptosis, and enhanced airway hyper-responsiveness (AHR) [3,8,9,10]. DRP1 is a cytosolic protein that, upon activation via phosphorylation and/or other post-translational modifications at key residues, localizes to the mitochondrial outer membrane at sites where the endoplasmic reticulum interacts with and preconstricts the mitochondrion. Several studies have suggested that mitochondria appear visually smaller in the airway epithelia of asthmatics or asthma mouse models, as seen via transmission electron microscopy [7,8]; the role of epithelial DRP1-mediated mitochondrial fission has yet to be fully elucidated in the allergic airway disease

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