B109-21 Aberrant Mitochondrial Fission Protein 1-Dependent Stress Responses Promote Mucoinflammatory Pathology in Cigarette Smoke-Associated COPD

Rationale

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway mucous hypersecretion and goblet cell hyperplasia, which are further exaggerated during disease exacerbations. Cigarette smoke (CS) remains the dominant environmental risk factor, yet the intracellular pathways linking CS exposure to airway epithelial remodeling remain incompletely understood. Emerging evidence implicates mitochondrial dysfunction as a central regulator of epithelial stress signaling and airway remodeling. Here, we investigated whether mitochondrial fission protein 1 (MTFP1) functions as a critical mediator linking mitochondrial stress responses to inflammatory and mucous remodeling in airway epithelial cells following CS exposure and assessed the CS-induced changes in lung tissues from COPD subjects and the animal model of CS exposure.

Methods

Primary human airway epithelial cells (HAECs) from COPD and non-COPD subjects were exposed to CS or cigarette smoke extract (CSE) to assess mitochondrial dynamics, oxidative stress, and mucous and inflammatory signaling. Bronchial biopsies from smokers and ex-smokers with and without COPD (stratified by GOLD-stage severity), as well as axial airways from CS-exposed mice, were analyzed for mitochondrial morphology, MTFP1 expression, oxidative stress (MitoSOX), and inflammatory mediators (IL-6, CXCL-8) using high-resolution microscopy and molecular assays. MTFP1 was suppressed using siRNA, and mitochondrial fission was pharmacologically inhibited with mDivi1. Changes in expression levels of airway mucous response (MUC5AC, FOXA3, SPDEF) and key mitochondrial fission (DRP1) and fusion (MFN2) regulators were quantified.

Results

CSE-induced MTFP1 activation in non-COPD HAECs was associated with heightened mitochondrial stress signaling, characterized by excessive fission, mtROS accumulation, and downstream proinflammatory transcriptional activation, and the levels were further augmented in COPD HAECs. In vivo, bronchial biopsies from COPD subjects and CS-exposed mice exhibited >4-fold higher expression of MTFP1 and MUC5AC levels, accompanied by altered mitochondrial morphology. The airway epithelial MTFP1 expression and mitochondrial redistribution strongly correlated with GOLD-stage disease severity among COPD smokers. CSE exposure induced FOXA3 and SPDEF, driving MUC5AC mucin expression. Genetic silencing of MTFP1 or pharmacologic inhibition of mitochondrial fission significantly attenuated CS-induced MUC5AC expression and mucous production, reduced mitochondrial ROS, and suppressed IL-6 and CXCL-8 expression.

Conclusions

Collectively, these data demonstrate that aberrant MTFP1-dependent mitochondrial stress responses drive airway mucoinflammatory pathology in cigarette smoke-associated COPD. Targeting airway epithelium- specific mitochondrial stress pathways may represent a novel therapeutic strategy to mitigate CS-driven mucoinflammatory responses and disease progression.

This abstract is funded by: None