Thiram-induced ER stress promotes mitochondrial calcium signaling and NLRP3 inflammasome activation in a tissue specific manner

Abstract

Thiram, a broadly used dithiocarbamate fungicide, exaggerates endoplasmic reticulum (ER) stress and interferes with mitochondrial function, thus disrupting cellular homeostasis. Here, we intend to identify the molecular actions of thiram at the mitochondrial-associated ER membranes (MAMs) that lead to the induction of ER stress and mitochondrial calcium overload in both liver and bone tissues. Taken together, we show that thiram-induced remodelling of MAMs leads to huge ER stress and calcium dysregulation. Histological and immunohistochemical examinations revealed that thiram-induced hyperactivation of IP3R1 mediated the release of endoplasmic reticulum calcium, but mitochondrial calcium uptake was mediated by voltage-dependent anion channels VDAC1. This stress response was characterized by increased glucose regulated protein 78 (GRP78) expression in the liver and tibial growth plates (GP). In this respect, a new liver-bone axis was delineated for thiram-induced ER stress. More interestingly, the activation of NLRP3 inflammasome was very striking in tibial growth plates but not in liver tissues. Hence, the results highlight the systemic effects of thiram by identifying a critical metabolic junction that might play a role in metabolic disorders such as tibial dyschondroplasia and related bone disorders, e.g., osteoarthritis and osteoporosis.