Cadmium-induced iron dysregulation contributes to functional impairment in brain endothelial cells via the ferroptosis pathway.

Abstract

Cadmium (Cd²⁺) is a heavy metal that is a major hazardous environmental contaminant, ubiquitously present in the environment. Cd²⁺ exposure has been closely associated with an increased prevalence and severity of neurological and cardiovascular diseases (CVD). The blood-brain barrier (BBB) plays a crucial role in protecting the brain from external environmental factors. Mitochondria play an important role in maintaining the barrier function of brain endothelial cells by regulating energy metabolism and redox homeostasis. In this study, we aimed to assess the cytotoxic effects of Cd²⁺ on the integrity and function of brain endothelial cells. After 24 h of exposure, Cd²⁺ reduced cell survival, tight junction protein expression, and trans-endothelial electrical resistance (TEER) in bEnd.3 cells suggest a potential BBB integrity disruption by Cd²⁺ exposure. To clarify the underlying mechanism, we further investigated the role of mitochondria in iron overload-mediated cell death following Cd²⁺ exposure. Cd²⁺ induced a substantial reduction in mitochondrial basal respiration and ATP production in brain endothelial cells, suggesting mitochondrial dysfunction. In addition, Cd²⁺ exposure led to impaired autophagy, elevated iron levels, and increased lipid peroxidation, indicating the initiation of ferroptosis, a form of cell death triggered by iron. In summary, our research suggests that Cd²⁺ exposure can disrupt BBB function by causing mitochondrial dysfunction and disrupting iron homeostasis.