The selenoprotein P/ApoER2 axis facilitates selenium accumulation in selenoprotein P-accepting cells and confers prolonged resistance to ferroptosis
Atsuya Ichikawa, Takashi Toyama, Hiroki Taguchi, Satoru Shiina, Hayato Takashima, Kazuaki W. TAKAHASHI, Yasumitsu Ogra, Ayako Mizuno, Kotoko Arisawa, Yoshiro Saito
Abstract
The essential trace element selenium (Se) plays a significant role in redox homeostasis, while Se is very reactive and has a potent toxicity. Understanding the molecular machinery that supports Se metabolism is important for the both physiological and pathophysiological context. Incorporated Se is translated/transformed in the liver into selenoprotein P (SeP; encoded by Selenop), an extracellular Se carrier protein that effectively transports Se to the cells via the binding to its receptor apolipoprotein E receptor 2 (ApoER2), which is taken up by cells. The present study shows that SeP is a source of Se that accumulates intracellularly and can be utilized for prolonged periods under Se-deficient conditions. In cultured cells (RD and SH-SY5Y), glutathione peroxidase (GPX) expression induced by Se supply via the SeP/ApoER2 pathway was maintained longer during Se deficiency than inorganic Se, which was promoted by ApoER2 overexpression. SeP-deficient mice showed a faster decline in brain Se levels when fed a Se-deficient diet. Preserved GPX expression induced by this SeP/ApoER2 axis contributed to oxidative stress and ferroptosis resistance, suggesting that this redundant Se metabolism contributes to prolonged Se utilization and cytoprotection.