2026/02/10 by Mohammad Irshad Reza, Cheyenne Tandberg, Ashish Kumar +6 · 1 voice
Biochemistry, Genetics and Molecular Biology · Environmental Science · #Eicosanoids and Hypertension Pharmacology #Heme Oxygenase-1 and Carbon Monoxide #Toxic Organic Pollutants Impact
paper · doi:10.1093/ajrcmb/aanag019
openalex publication_date 2026/02/10 · openalex created_date 2026/02/22 · openalex updated_date 2026/08/04
In asthma, pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFα) drive excessive mitochondrial fission in ASM cells through activating dynamin-related protein 1 (DRP1). Recently, we demonstrated that aryl hydrocarbon receptor (AhR) is expressed in human ASM and is upregulated during inflammation and asthma. This study explores the role of AhR in regulating mitochondrial fission in human ASM cells under pro-inflammatory and asthmatic conditions. Primary human nonasthmatic and asthmatic ASM cells were treated with 6-formylindolo[3,2-b]carbazole (FICZ: AhR agonist), with or without TNFα. Mitochondrial morphology was assessed using MitoTracker staining. DRP1 expression was evaluated in whole-cell and mitochondrial fractions. Loss- and gain-of-function studies (AhR inhibition, knockdown, and overexpression) were performed. AhR binding on the DRP1 promoter and promoter activity were assessed by ChIP-qPCR and luciferase reporter. The effects of AhR activation on oxygen consumption rate (OCR) were analyzed using seahorse XF-Pro. AhR activation significantly inhibited TNFα- and asthma-induced mitochondrial fission in ASM cells via inhibiting DRP1 in both inactive and active forms. In contrast, AhR inhibition or knockdown aggravated mitochondrial fission, while AhR overexpression failed to prevent TNFα-induced fission without ligand activation. Mechanistically, AhR bound the DRP1 promoter and suppressed its promoter activity, consistent with a genomic mode of action, while failing to alter ERK1/2 phosphorylation. Additionally, AhR activation also reduced TNFα- and asthma-induced increase in OCR. Collectively, this study shows that AhR activation prevents mitochondrial fission by inhibiting DRP1 in ASM during inflammation and highlights AhR as a promising therapeutic target for asthma and other airway diseases associated with mitochondrial dysfunction.