Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation.
Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation.
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线粒体柠檬酸盐代谢和流出调节滋养层分化。
DOI：
10.1101/2023.01.22.525071
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Wernimont,SarahA
中科院分区：
文献类型：
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作者：
Mahr,ReneeM;Jena,Snehalata;Nashif,SereenK;Nelson,AlisaB;Rauckhorst,AdamJ;Rome,FerrolI;Sheldon,RyanD;Hughey,CurtisC;Puchalska,Patrycja;Gearhart,MicahD;Taylor,EricB;Crawford,PeterA;Wernimont,SarahA
细胞滋养层融合形成并更新合体滋养层，维持整个妊娠期胎盘的健康。在细胞滋养层向合胞体滋养层分化期间，细胞经历受调节的代谢和转录重编程。线粒体在细胞系统中的分化事件中起着关键作用，因此我们假设线粒体代谢在滋养层分化中起着核心作用。在这项工作中，我们采用静态和稳定同位素示踪非靶向代谢组学方法沿着与基因表达和组蛋白乙酰化研究在一个建立的细胞培养模型的滋养层分化。滋养层分化与TCA循环中间体柠檬酸和α-酮戊二酸丰度增加相关。柠檬酸盐优先从未分化状态的线粒体中输出，但在分化后在线粒体内保留更大程度。相应地，分化与线粒体柠檬酸盐转运蛋白（CIC）的表达减少有关。CRISPR/Cas9对线粒体柠檬酸盐载体的破坏表明，CIC是滋养层生物化学分化所必需的。CIC的丢失导致基因表达和组蛋白乙酰化的广泛改变。这些基因表达的变化部分通过乙酸盐补充被挽救。总之，这些结果突出了线粒体柠檬酸盐代谢在滋养层分化过程中协调组蛋白乙酰化和基因表达的核心作用。
Cytotrophoblasts fuse to form and renew syncytiotrophoblasts necessary to maintain placental health throughout gestation. During cytotrophoblast to syncytiotrophoblast differentiation, cells undergo regulated metabolic and transcriptional reprogramming. Mitochondria play a critical role in differentiation events in cellular systems, thus we hypothesized that mitochondrial metabolism played a central role in trophoblast differentiation. In this work, we employed static and stable isotope tracing untargeted metabolomics methods along with gene expression and histone acetylation studies in an established cell culture model of trophoblast differentiation. Trophoblast differentiation was associated with increased abundance of the TCA cycle intermediates citrate and α-ketoglutarate. Citrate was preferentially exported from mitochondria in the undifferentiated state but was retained to a larger extent within mitochondria upon differentiation. Correspondingly, differentiation was associated with decreased expression of the mitochondrial citrate transporter (CIC). CRISPR/Cas9 disruption of the mitochondrial citrate carrier showed that CIC is required for biochemical differentiation of trophoblasts. Loss of CIC resulted in broad alterations in gene expression and histone acetylation. These gene expression changes were partially rescued through acetate supplementation. Taken together, these results highlight a central role for mitochondrial citrate metabolism in orchestrating histone acetylation and gene expression during trophoblast differentiation.