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Published on: July 10, 2018
PM2.5 enhances DRP1-mediated mitochondrial fission to induce ferroptosis and exacerbate asthma through the
Simiao Qiao1, Fanshu Li1, Jia Huang1
1Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
Abstract:
This study was designed to clarify the reason for PM2.5 to induce the ferroptosis of bronchial epithelial cells and worsen asthma in detail, advancing the development of relevant drugs. Results displayed that PM2.5 mainly induced ferroptosis but not apoptosis of bronchial epithelial cells, indicating by the changes of lipid reactive oxygen species (ROS), iron, malondialdehyde, lactic dehydrogenase, nuclear receptor coactivator 4, glutathione and glutathione peroxidase 4 levels, and further confirmed by using in combination with the ferroptosis and apoptosis inhibitors. It also caused the mitochondrial disturbance, reduced the level of mitochondrial membrane potential, up-regulated the level of mitochondrial ROS, and mechanisms were subsequently ascribed to dynamin-related protein 1 (DRP1)-related mitochondrial fission. Furthermore, the up-regulation on ubiquitination of pyruvate kinase M2 (PKM2) but not macrophage stimulating 1 or interferon regulatory factor 1, the transcriptional regulators locating at the upstream of DRP1, was showed by PM2.5via controlling "aryl hydrocarbon receptor (AHR)-heat shock protein 90 (HSP90)" axis. In addition, isoliquiritigenin (ISL), the main active ingredients in licorice, was demonstrated to prevent the PM2.5-induced activation of AHR-PKM2-ferroptosis in asthma. In conclusion, PM2.5 activated "AHR-HSP90" axis to disturb DRP1-related mitochondrial fission, induced ferroptosis of bronchial epithelial cells, and worsened asthma. Conversely, ISL restored the above-mentioned signals, ferroptosis and asthma mediated by PM2.5, and was suggested as a potential compound to combat the exacerbation of asthma.
Insights
Particulate matter (PM2.5) triggers ferroptosis in airway cells, worsening asthma via mitochondrial dysfunction. Isoliquiritigenin (ISL) offers a potential treatment by blocking this PM2.5-induced pathway.
Area of Science:
- Environmental Health
- Cell Biology
- Pulmonology
Background:
- Asthma exacerbation is frequently linked to exposure to fine particulate matter (PM2.5).
- The precise cellular mechanisms by which PM2.5 impacts airway cells and asthma severity remain incompletely understood.
- Ferroptosis, a form of regulated cell death, is implicated in various inflammatory conditions.
Purpose of the Study:
- To elucidate the detailed mechanisms by which PM2.5 induces ferroptosis in bronchial epithelial cells.
- To investigate the role of mitochondrial dynamics and specific molecular pathways in PM2.5-induced cell death.
- To evaluate the therapeutic potential of isoliquiritigenin (ISL) in mitigating PM2.5-driven asthma exacerbation.
Main Methods:
- Assessed PM2.5 effects on bronchial epithelial cells, measuring markers of ferroptosis (lipid ROS, iron, MDA, LDH, NCO4, GSH, GPX4) and apoptosis.
- Utilized ferroptosis and apoptosis inhibitors to confirm cell death pathways.
- Investigated mitochondrial function (membrane potential, mitochondrial ROS) and related proteins (DRP1).
- Examined the involvement of the aryl hydrocarbon receptor (AHR)-heat shock protein 90 (HSP90) axis and pyruvate kinase M2 (PKM2) ubiquitination.
- Tested the protective effects of isoliquiritigenin (ISL) in PM2.5-exposed asthma models.
Main Results:
- PM2.5 primarily induced ferroptosis, not apoptosis, in bronchial epithelial cells, evidenced by altered biochemical markers and confirmed with inhibitors.
- PM2.5 disrupted mitochondrial function, leading to decreased membrane potential and increased mitochondrial ROS, mediated by DRP1-dependent mitochondrial fission.
- PM2.5 upregulated PKM2 ubiquitination via the AHR-HSP90 pathway, upstream of DRP1 activation.
- Isoliquiritigenin (ISL) effectively inhibited PM2.5-induced AHR-PKM2-ferroptosis signaling and ameliorated asthma symptoms in vivo.
Conclusions:
- PM2.5 exacerbates asthma by activating the AHR-HSP90 pathway, disrupting mitochondrial dynamics, and inducing ferroptosis in bronchial epithelial cells.
- Isoliquiritigenin (ISL) demonstrates significant potential as a therapeutic agent against PM2.5-induced asthma exacerbation by reversing these detrimental effects.
- This study provides critical insights into the molecular pathogenesis of PM2.5-induced airway inflammation and offers a novel therapeutic target.
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