Fatty acid synthesis is critical for stem cell pluripotency via promoting mitochondrial fission
Fatty acid synthesis is critical for stem cell pluripotency via promoting mitochondrial fission
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脂肪酸合成通过促进线粒体裂变对干细胞多能性至关重要
DOI：
10.15252/embj.201695417
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发表时间：
2017-05-15
期刊：
影响因子：
11.4
通讯作者：
Gao, Ping
中科院分区：
文献类型：
--
作者：
Wang, Lihua;Zhang, Tong;Gao, Ping
已知多能干细胞显示出与其体细胞对应物不同的代谢表型。虽然越来越多的研究集中在葡萄糖和氨基酸代谢在促进多能性中的作用，但关于脂质代谢在调节干细胞活性中的作用知之甚少。在这里，我们表明，脂肪酸（FA）合成激活是干细胞多能性的关键。我们最初的观察表明，在多能细胞和细胞重编程过程中，脂肪生成增强。进一步的分析表明，从头FA合成控制细胞重编程和胚胎干细胞多能性通过线粒体分裂。从机制上讲，我们发现由脂肪生成酶ACC 1调节的从头FA合成通过（i）AcCoA的消耗（影响乙酰化介导的FIS 1泛素-蛋白酶体降解）和（ii）脂质产物的产生（驱动线粒体动态平衡朝向分裂）导致线粒体分裂增强。此外，我们证明了Acc 1通过线粒体分裂对细胞重编程的影响也存在于人iPSC诱导中。总之，我们的研究揭示了FA合成途径通过调节线粒体分裂促进ESC多能性和iPSC形成的关键参与。
Pluripotent stem cells are known to display distinct metabolic phenotypes than their somatic counterparts. While accumulating studies are focused on the roles of glucose and amino acid metabolism in facilitating pluripotency, little is known regarding the role of lipid metabolism in regulation of stem cell activities. Here, we show that fatty acid (FA) synthesis activation is critical for stem cell pluripotency. Our initial observations demonstrated enhanced lipogenesis in pluripotent cells and during cellular reprogramming. Further analysis indicated that de novo FA synthesis controls cellular reprogramming and embryonic stem cell pluripotency through mitochondrial fission. Mechanistically, we found that de novo FA synthesis regulated by the lipogenic enzyme ACC1 leads to the enhanced mitochondrial fission via (i) consumption of AcCoA which affects acetylation‐mediated FIS1 ubiquitin–proteasome degradation and (ii) generation of lipid products that drive the mitochondrial dynamic equilibrium toward fission. Moreover, we demonstrated that the effect of Acc1 on cellular reprogramming via mitochondrial fission also exists in human iPSC induction. In summary, our study reveals a critical involvement of the FA synthesis pathway in promoting ESC pluripotency and iPSC formation via regulating mitochondrial fission.