Abstract
Melatonin protects against Cadmium (Cd)-induced toxicity, a ubiquitous environmental toxicant that causes adverse health effects by increasing reactive oxygen species (ROS) production and mitochondrial dysfunction. However, the underlying mechanism remains unclear. Here, we demonstrate that Cd exposure reduces the levels of mitochondrially-localized signal transducer and activator of transcription 3 (mitoSTAT3) using human prostate stromal cells and mouse embryonic fibroblasts. Melatonin enhances mitoSTAT3 abundance following Cd exposure, which is required to attenuate ROS damage, mitochondrial dysfunction, and cell death caused by Cd exposure. Moreover, melatonin increases mitochondrial levels of GRIM-19, an electron transport chain component that mediates STAT3 import into mitochondria, which are downregulated by Cd. In vivo, melatonin reverses the reduced size of mouse prostate tissue and levels of mitoSTAT3 and GRIM-19 induced by Cd exposure. Together, these data suggest that melatonin regulates mitoSTAT3 function to prevent Cd-induced cytotoxicity and could preserve mitochondrial function during Cd-induced stress.