Unraveling the dual-hit mitochondrial assault in COPD: Synergistic RISP-targeted disruption by nicotine and Pseudomonas pyoverdine

Chronic obstructive pulmonary disease (COPD) relentlessly devastates global health, with Pseudomonas aeruginosa (PA) colonization accelerating mortality and exacerbations through enigmatic molecular pathways. We present a paradigm-shifting discovery: nicotine and PA’s virulence factor pyoverdine collaboratively assault the mitochondrial Rieske iron-sulfur protein (RISP) in airway smooth muscle cells, unleashing a synergistic storm of reactive oxygen species (ROS) that cripples ATP synthesis and drives the core pathophysiology of COPD. Leveraging sophisticated smooth muscle-specific RISP knockout and overexpression models with rigorous sex-stratified analysis, we subjected mice to nicotine, wild-type and pyoverdine-deficient PA, and their lethal combination. This dual-hit insult triggered a 1.8-fold surge in mitochondrial ROS—far surpassing additive predictions (1.65-fold, Bliss Independence; 9.1-fold amplification, p < 0.001)—and provoked a devastating 25–40% decline in FEV/FVC ratio, elevated airway resistance, and dynamic compliance loss, with males exhibiting 25–35% greater vulnerability. Crucially, RISP deletion obliterated this pulmonary collapse, whereas overexpression aggravated dysfunction by up to 40%, unequivocally establishing RISP as the linchpin of mitochondrial and functional derangement. Pharmacological intervention with the mitochondrial ROS inhibitor S3QEL rescued up to 60% of lung function, conclusively pinpointing a ROS-dependent mechanism. Pioneering CRISPR-engineered RISP iron-sulfur cluster mutants revealed structural integrity alone governs susceptibility to pyoverdine-induced damage; these mutants manifested 60–80% exacerbated dysfunction reversed by 50–70% iron chelation. Robust correlations (r ≥ 0.8) between mitochondrial impairment, ROS load, and lung function forge RISP integrity as a biomarker intimately linking host-pathogen dynamics to disease severity. This transformative work defines mitochondrial Complex III RISP as the first actionable nexus coordinating environmental and microbial genesis of COPD, propelling a bold new era of precision therapeutics that stratify and shield vulnerable PA-colonized patients. Supported by NIH/NHLBI and American Thoracic Society Foundation funding, this research revolutionizes COPD treatment, transcending symptom palliation toward true mechanistic cure. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.