Mitochondrial dysfunction and the regulatory cell death crosstalk network in chronic obstructive pulmonary disease: from oxidative stress mechanisms to targeted therapeutic strategies

Abstract

The sustained progression of chronic obstructive pulmonary disease (COPD) may not be independently driven by a single process such as chronic inflammation, oxidative stress, or cell death, but rather originates from a cross-amplification network among “mitochondrial dysfunction-oxidative stress-regulated cell death.” In the context of mitochondrial damage, excessive generation of reactive oxygen species (ROS), damage and release of mitochondrial DNA (mtDNA), and dysregulation of mitochondrial quality control (MQC) collectively promote airway epithelial injury, sustained inflammation, alveolar destruction, and tissue remodeling. Furthermore, regulated cell death modalities such as apoptosis, necroptosis, pyroptosis, and ferroptosis are not isolated from each other but are coupled under a shared context of mitochondrial stress, exhibiting different dominant patterns across various cell types and disease stages. Adopting an integrated perspective encompassing mitochondrial dysfunction, amplified oxidative stress, and the regulated cell death (RCD) cross-network, this article synthesizes current research regarding COPD-related mechanisms, with a focus on mitochondrial damage markers, RCD activity indicators, mechanism-oriented patient stratification, and potential therapeutic strategies targeting mitochondrial homeostasis and cell death pathways. This framework facilitates the transition of COPD understanding from the traditional chronic inflammation model to a more stratified and translationally promising mitochondrial-cell death network model.