Slc25a36 modulates pluripotency of mouse embryonic stem cells by regulating mitochondrial function and glutathione level
Slc25a36 modulates pluripotency of mouse embryonic stem cells by regulating mitochondrial function and glutathione level
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Slc25a36通过调节线粒体功能和谷胱甘肽水平来调节小鼠胚胎干细胞的多能性
DOI：
10.1042/bcj20190057
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发表时间：
2019
影响因子：
4.1
通讯作者：
Han Jianyong
中科院分区：
文献类型：
--
作者：
Xin Yanli;Wang Yanliang;Zhong Liang;Shi Bingbo;Liang Hui;Han Jianyong
线粒体在维持胚胎干细胞的初始状态中起着核心作用。这一机制的许多细节仍有待充分阐明。溶质载体家族25成员36 （Slc25a36）可能通过转运嘧啶核苷酸合成mtDNA/RNA来调节线粒体功能。它在这一过程中的物理作用尚不清楚；然而，slc25a36最近被发现在小鼠胚胎干细胞（mESCs）中高表达。在这里，slc25a36的功能被表征为mESCs多能性的维持因子。slc25a36缺陷（通过敲低）已被证明会导致线粒体功能障碍，从而诱导mESCs的分化。关键多能性标记（Pou5f1、Sox2、Nanog、utf1）表达减少，而关键TE基因（Cdx2、Gata3、hand1）表达增加。在滋养细胞干细胞培养条件下，cdx2阳性细胞出现在slc25a36缺失的菌落中。由于slc25a36缺乏，敲低细胞的mtDNA下降，导致线粒体受损，形态肿胀，线粒体膜电位下降，数量减少。线粒体生物发生的关键转录调控因子也减少。这些结果表明，线粒体功能障碍导致无法支持多能性维持。谷胱甘肽代谢下调和局灶黏附上调分别通过增强OCT4降解和促进细胞扩散来增强和稳定分化过程。本研究提高了对slc25a36功能的认识，以及线粒体功能与原始多能性维持和干细胞命运决定的关系。
Mitochondria play a central role in the maintenance of the naive state of embryonic stem cells. Many details of the mechanism remain to be fully elucidated. Solute carrier family 25 member 36 (Slc25a36) might regulate mitochondrial function through transporting pyrimidine nucleotides for mtDNA/RNA synthesis. Its physical role in this process remains unknown; however,Slc25a36was recently found to be highly expressed in naive mouse embryonic stem cells (mESCs). Here, the function ofSlc25a36was characterized as a maintenance factor of mESCs pluripotency.Slc25a36deficiency (via knockdown) has been demonstrated to result in mitochondrial dysfunction, which induces the differentiation of mESCs. The expression of key pluripotency markers (Pou5f1,Sox2,Nanog, andUtf1) decreased, while that of key TE genes (Cdx2,Gata3, andHand1) increased.Cdx2-positive cells emerged inSlc25a36-deficient colonies under trophoblast stem cell culture conditions. As a result ofSlc25a36 deficiency, mtDNA of knockdown cells declined, leading to impaired mitochondria with swollen morphology, decreased mitochondrial membrane potential, and low numbers. The key transcription regulators of mitochondrial biogenesis also decreased. These results indicate that mitochondrial dysfunction leads to an inability to support the pluripotency maintenance. Moreover, down-regulated glutathione metabolism and up-regulated focal adhesion reinforced and stabilized the process of differentiation by separately enhancing OCT4 degradation and promoting cell spread. This study improves the understanding of the function ofSlc25a36, as well as the relationship of mitochondrial function with naive pluripotency maintenance and stem cell fate decision.