Pneumoconiosis, characterized by progressive pulmonary fibrosis, remains a predominant occupational disease in China, with coal workers’ pneumoconiosis (CWP) and silicosis being the primary subtypes. Despite extensive research, its underlying pathogenic mechanisms are not yet fully understood. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are crucial subcellular microdomains that govern Ca2+ transport, sustain cellular bioenergetics, and maintain systemic homeostasis. Emerging evidence has linked the structural and functional dysregulation of MAMs to the pathogenesis of various fibrotic disorders. Apoptosis, a highly regulated cell death process, is a key driver in pneumoconiosis progression, in which Ca2+ imbalance serves as a critical signaling cascade. Mitofusin 2 (MFN2), a core regulator of MAMs’ structural integrity, mediates mitochondrial fusion and directly bridges the ER with the outer mitochondrial membrane, thereby stabilizing ER–mitochondrial coupling. However, whether MFN2 mitigates fibrosis by preserving MAMs’ integrity and subsequently suppressing Ca2+-dependent apoptosis remains elusive. In this study, we established SD rat and A549 cell models of CWP. Our results demonstrated that MFN2 expression was downregulated after coal dust exposure, accompanied by MAMs impairment, Ca2+ imbalance, and increased apoptosis, which ultimately drove the pathological progression of pulmonary fibrosis. Notably, MFN2 overexpression restored MAMs’ structure and Ca2+ homeostasis, alleviated abnormal apoptosis, and subsequently inhibited fibrosis. This study highlights the importance of the MFN2–MAMs–Ca2+–apoptosis axis and identifies MFN2 as a potential therapeutic target for pneumoconiosis.
Zhang et al. (Thu,) studied this question.