Selenoprotein K Confers Protection against Iron Dyshomeostasis-Related Neurotoxicity by Regulating the Palmitoylation of TfR-1

Selenoprotein K (SELENOK), a protein residing in the endoplasmic reticulum (ER), is modulated by dietary selenium and is expressed at elevated levels in neurons. SELENOK has been shown to participate in cellular antioxidant activity and posttranslational palmitoylation. This study presents both in vivo and in vitro evidence that SELENOK deficiency reduces the palmitoylation of TfR-1, thereby impairing transferrin transport and ultimately leading to a decrease in the intracellular iron content, impaired mitochondrial respiratory chain activity and decreased ATP production. Remarkably, restoring SELENOK levels significantly enhanced TfR-1 palmitoylation, increased intracellular iron levels, and restored mitochondrial function, thus ameliorating cognitive deficits in 7 month-old SELENOK knockout mice. Consistent with these findings, iron supplementation also improved mitochondrial function by elevating intracellular iron levels, thereby improving cognitive deficits in 7 month-old SELENOK knockout mice. Therefore, SELENOK exerts its neuroprotective effect by regulating the palmitoylation of TfR-1 to maintain iron homeostasis, thereby protecting mitochondrial function in neurons.