DRP1-Mediated Mitochondrial Fission Regulates Lung Epithelial Response to Allergen

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.

Deletion of Miro1 in airway club cells potentiates allergic asthma phenotypes

“…The role of Miro1-mediated mitochondrial trafficking upon exposure to a complex allergen in airway epithelial cells, and their associated inflammatory responses, had not been demonstrated in previous literature. Our results provide compelling evidence for the role of Miro1 in airway epithelial cells by mediating inflammatory responses associated with HDM exposure and build upon our previous studies showing the importance of mitochondrial DRP1 to this process ( 23 ). However, the mechanistic details underlying the observed phenotype remain unclear, including additional aspects of Miro1 biology ( 54 , 55 ) that where next explored in this study.…”

“…More specifically, IL-6 and IL-33, two pro-inflammatory cytokines produced by airway epithelia known to play key roles in severity of asthma inflammation ( 20 , 21 ), were modestly yet significantly upregulated in HDM-exposed mice following Miro1 deletion in club cells when compared to Ctrl HDM-challenged mice ( Figures 3A,B ). Further, the chemokine CCL20, produced by airway epithelial cells and known to play a significant role in mucus metaplasia, eosinophil recruitment, and IgE production in response to allergen ( 22 , 23 ), was also significantly upregulated in HDM-exposed Miro1 -deleted mice compared to Ctrls . ( Figure 3C ).…”

“…As a result, these double-membraned organelles change in size, shape, and distribution depending on intracellular mitochondrial metabolite demands ( 20 – 22 ). Our previous work showed that mitochondrial fission is an early event following exposure of bronchial epithelial cells to house dust mite and that knockout of the pro-fission protein Dynamin Related Protein 1 (DRP1) exacerbates asthmatic phenotypes ( 23 ). Within the cell, mitochondria are transported on the microtubule-associated molecular motors kinesin and dynein ( 24 – 26 ), and tethered to these motors by a protein complex composed of trafficking kinesin protein 1 and 2 (TRAK1/2) and Mitochondrial Rho GTPase 1 and 2 (Miro1/2) ( 27 – 32 ).…”

Mitochondrial dynamics modulate the allergic inflammation in a murine model of allergic rhinitis

“…12,15 Upon activation by endogenous or exogenous stimulation, Drp1 accumulates in the mitochondrial outer membrane, leading to mitochondrial fragmentation and further ROS generation. 16,17 Emerging evidence suggests that overactivation of Drp1 and mitochondrial fragmentation may play a role in progression of allergic diseases, [18][19][20] perturbing the normal functions of T cells, mast cells, and NK cells. 18,21 ROS derived from mitochondrial disfunction have been proposed to promote Th2 polarization, impaired the IFN-γ expression, and heightened allergic responses through activation of JAKs and STAT6.…”

Editorial of Special Issue “Molecular Mechanisms of Allergy and Asthma”

“…Their results suggested that being associated with a thicker reticular basement membrane, the pro-fibrotic profile in the airway epithelial cell transcriptome might contribute to asthma airway remodeling. In a methodologically robust study, Bruno and colleagues [4] demonstrated the importance of dynamin related protein 1-mediated mitochondrial fission for regulation of the pro-inflammatory response by respiratory epithelium and airway epithelial cell survival after exposure to house dust mites. Richards and co-workers [5] showed that short-chain fatty acids, fermentation metabolites from the gut microbiome, contributed to the recovery of barrier properties of airway epithelial cells, which might be mediated by increasing the expression of zonula occludens-1, a tight junction protein contributing to the integrity of the epithelium.…”