Investigating the mechanism by which telomere dysfunction affects mitochondrial homeostasis in anthracosilicosis using a Terc knockout model.

Abstract

Anthracosilicosis, a type of coal workers' pneumoconiosis, exhibits pathological features of both coal workers' pneumoconiosis and silicosis. Its pathogenesis remains incompletely understood. Growing evidence suggests that telomere dysfunction and mitochondrial homeostasis play critical roles in the development of pulmonary fibrosis. This study aimed to investigate the regulatory role of telomere function in mitochondrial homeostasis and its impact on pulmonary fibrosis in anthracosilicosis, using a telomerase RNA component (Terc) knockout mouse model. Terc knockout mice and an anthracosilicosis mouse model were established to explore the effects of telomere function on mitochondrial homeostasis. Lung tissues were subjected to histopathological analysis via H&E and Masson staining. Deposition of COL1a1 and COL1a3 was detected using immunofluorescence. Telomere length was measured by quantitative fluorescence in situ hybridization (Q-FISH) and qPCR. Subcellular localization of telomerase reverse transcriptase (TERT) to mitochondria was observed via immunofluorescence colocalization. Mitochondrial ultrastructural changes were assessed using transmission electron microscopy (TEM). Oxidative stress levels were evaluated by ELISA and ferric reducing antioxidant power (FRAP) assays. Expression levels of six telomere-binding proteins and mitochondrial homeostasis-related markers were analyzed by Western blot and qPCR. Compared with control and coal-silica dust (CSD)-exposed wild-type mice, Terccontrol and TercCSD-exposed mice exhibited significantly shortened telomeres, severe dysregulation of six telomere-binding proteins, and exacerbated telomere dysfunction. These mice also showed enhanced oxidative damage, abnormal mitochondrial morphology and quantity under TEM, significantly reduced ATP levels, and disrupted mitochondrial dynamic balance. Our findings demonstrate that coal-silica dust exposure aggravates telomere shortening and disrupts mitochondrial homeostasis in Tercmice, leading to exacerbated pulmonary fibrosis and promoting the initiation and progression of anthracosilicosis. These results provide valuable insights for developing precise prevention and treatment strategies for pneumoconiosis.