Jia Shi-Zheng, Li Yu, Xu Xin-Wen, Huang Yan-Ping, Deng Xiao-Yi, Zhang Zhong-Hao, Song Guo-Li
Shenzhen Key Laboratory of Marine Bioresources and Ecology, Brain Disease and Big Data Research Institute, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China.
Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen 518060, China.
J Agric Food Chem. 2025 May 21;73(20):12233-12246. doi: 10.1021/acs.jafc.4c08266. Epub 2025 Apr 28.
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.
硒蛋白K（SELENOK）是一种存在于内质网（ER）中的蛋白质，受膳食硒调节，在神经元中表达水平升高。已证明SELENOK参与细胞抗氧化活性和翻译后棕榈酰化。本研究提供了体内和体外证据，表明SELENOK缺乏会降低转铁蛋白受体1（TfR-1）的棕榈酰化，从而损害转铁蛋白运输，最终导致细胞内铁含量降低、线粒体呼吸链活性受损和ATP生成减少。值得注意的是，恢复SELENOK水平可显著增强TfR-1的棕榈酰化，提高细胞内铁水平，并恢复线粒体功能，从而改善7月龄SELENOK基因敲除小鼠的认知缺陷。与这些发现一致，补充铁也通过提高细胞内铁水平改善了线粒体功能，从而改善了7月龄SELENOK基因敲除小鼠的认知缺陷。因此，SELENOK通过调节TfR-1的棕榈酰化来维持铁稳态，从而保护神经元中的线粒体功能，发挥其神经保护作用。
