Mitochondrial-endoplasmic reticulum interactions in lung diseases

Abstract The pathogenesis of lung diseases is highly complex and multifactorial, posing a persistent challenge to global public health, while effective therapeutic options remain limited. Therefore, systematically elucidating the cellular and molecular mechanisms underlying lung injury is a crucial prerequisite for developing novel therapeutic strategies. Accumulating evidence highlights that the endoplasmic reticulum and mitochondria are key organelles driving the progression of lung injury. Notably, mitochondria-associated membranes (MAMs) form a structural and functional bridge between the endoplasmic reticulum and mitochondria, highlighting the essential role of inter-organellar communication in maintaining lung function homeostasis. This review comprehensively summarizes the autonomous mechanisms of the mitochondria and endoplasmic reticulum in lung injury-related diseases, with a further focus on the complex architecture and regulatory mechanisms of MAMs. It emphasizes the molecular mechanisms by which dysfunctional MAMs contribute to the onset and progression of lung injury, including Ca²⁺ signaling, oxidative stress, lipid synthesis and transport, UPR ER and UPR mt , mitochondrial homeostasis, and cell death. Finally, incorporating recent research advances, we discuss the current challenges and future prospects in this field, with particular emphasis on intervention strategies targeting Ca²⁺ transport at MAMs, mitochondrial quality control, endoplasmic reticulum stress, and metabolic coupling, as well as their potential for clinical translation. Overall, a deeper understanding of the functional interaction network among mitochondria, the endoplasmic reticulum, and their associated MAMs is expected to provide a robust theoretical foundation and translational insights for elucidating novel molecular mechanisms underlying lung injury and optimizing therapeutic strategies.