Laboratory of Cell Function Regulation, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, South Korea; Institute of Animal Molecular Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, South Korea.
Department of Pathology, College of Medicine, Korea University Guro Hospital, Seoul, 08308, South Korea.
Metab Eng. 2019 May;53:35-47. doi: 10.1016/j.ymben.2019.02.003. Epub 2019 Feb 16.
Reprogramming of 'adult' differentiated somatic cells to 'embryonic' pluripotent stem cells accompanied by increased rate of glycolysis. Conversely, glycolysis triggers accumulation of advanced glycation end products (AGEs), a potential causative factor in aging, by promoting methylglyoxal production. Therefore, it is reasonable that pluripotent stem cells (PSCs) would specifically regulate glycolysis to maintain their embryonic features. In this study, we focused on glycine decarboxylase (GLDC), a key enzyme in the glycine cleavage system that regulates glycolysis and methylglyoxal production in cancer. GLDC was exclusively expressed in PSCs, and inhibition of this enzyme induced alterations of metabolome and AGE accumulation, thereby suppressing the embryonic pluripotent state. Surprisingly, the level of accumulated AGEs in somatic cells gradually decreased during reprogramming, ultimately disappearing in iPSCs. In addition, ectopic expression of GLDC or treatment with the AGE inhibitor LR-90 promoted reprogramming. Together, these findings suggest that GLDC-mediated regulation of glycolysis and controlling AGE accumulation is related to maintenance and induction of pluripotency.
重编程“成年”分化体细胞为“胚胎”多能干细胞伴随着糖酵解速率的增加。相反，糖酵解通过促进甲基乙二醛的产生，触发晚期糖基化终产物 (AGEs) 的积累，AGEs 是衰老的一个潜在致病因素。因此，多能干细胞 (PSCs) 会特异性地调节糖酵解以维持其胚胎特征是合理的。在这项研究中，我们专注于甘氨酸脱羧酶 (GLDC)，它是糖裂解系统中的关键酶，可调节癌症中的糖酵解和甲基乙二醛的产生。GLDC 仅在 PSCs 中表达，抑制该酶会诱导代谢组的改变和 AGE 的积累，从而抑制胚胎多能状态。令人惊讶的是，体细胞中积累的 AGEs 水平在重编程过程中逐渐降低，最终在 iPSCs 中消失。此外，GLDC 的异位表达或用 AGE 抑制剂 LR-90 处理可促进重编程。总之，这些发现表明，GLDC 介导的糖酵解调节和 AGE 积累的控制与多能性的维持和诱导有关。
