Autophagy, Apoptosis, and Inflammatory Mechanisms in Chronic Respiratory Diseases: Interplay in Special Reference to Mitochondrial‐ER Stress Axis

Chronic respiratory diseases (CRDs) such as asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung cancer, along with other CRDs, continue to be a major cause of morbidity and mortality globally and constitute a growing global health burden. There is growing evidence that the etiology of these conditions is primarily driven by organelle stress, specifically mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Mitochondria, which are highly susceptible to environmental stressors such as hypoxia, pollution, and tobacco smoke, can fail, leading to epithelial cell apoptosis, metabolic dysregulation, fibrosis, excessive mitochondrial reactive oxygen species (mtROS), altered calcium signaling, and impaired mitophagy. Similarly, unresolved ER stress triggers maladaptive unfolded protein response signaling, which in turn promotes epithelial damage, mucus hypersecretion, fibroblast activation, and tumor growth. Through ROS signaling and calcium flux, crosstalk between the mitochondria and the ER amplifies these maladaptive pathways. Dysregulated autophagy can promote tissue remodeling, inflammation, and tumor survival when it is either impaired or excessive. Another layer is added by apoptosis, which upsets tissue homeostasis by excessive fibroblast survival or epithelial cell death. Chronic inflammation is fueled by immune dysregulation and perpetual organelle stress, which exacerbates disease progression and resistance to therapy. Promising treatment options include adenosine monophosphate-activated protein kinase - mammalian target of rapamycin (AMPK-mTOR) regulators, ER stress modulators, mitochondrial-targeted antioxidants, and immunometabolic therapies that target organelle stress pathways. This review summarizes current insights into organelle stress responses in CRDs, with a focus on their integration with autophagy, apoptosis, and inflammation, and highlights the future approaches for precision medicine therapies aimed at alleviating disease burden.