Mitochondrial reprogramming of neutrophil extracellular traps in chronic obstructive pulmonary disease and asthma: toward a phenotype-driven therapeutic framework.

Chronic obstructive pulmonary disease (COPD), severe asthma, and asthma-COPD overlap (ACO) represent a major global burden of chronic airway inflammation, often remaining inadequately controlled by current corticosteroid and biologic therapies. Neutrophil extracellular traps (NETs) have emerged as a shared effector mechanism in these phenotypes, with neutrophil mitochondria acting as the upstream switch for sustained NET release and corticosteroid resistance. This review consolidates evidence that mitochondrial reprogramming of NETosis operates through four interlinked facets: mitochondrial reactive oxygen species (mtROS) production, the mitochondrial permeability transition pore, mitochondrial DNA release (mtDNA-DAMP), and PINK1/Parkin-PGC-1α-controlled mitophagy. These mechanisms drive a downstream spectrum including suicidal NETosis, vital mtDNA-NETosis, and gasdermin-mediated discharge. Disease-specific drivers (e.g., Nrf2-SLC7A11-GPX4 in COPD; IL-33/TSLP in asthma) reweight this common axis, resulting in distinct effector repertoires and steroid-response profiles. Therapeutically, the landscape is asymmetric: whilst NET-dissolution agents and type-2 biologics are approved, they address distal nodes. Conversely, mitochondrial-targeted antioxidants and metabolic regulators target the convergent root but remain in early development. We argue that translating this framework requires phenotype-enriched trials randomizing molecularly selected patients, coordinated bedside biomarker panels, and explicit inclusion of the ACO subgroup. A coherent framework, a set of candidate targets, and an explicit stratification logic are now defined, and the pivotal preclinical and early-phase clinical data needed to deliver such a programme are the necessary next step.