Department of Molecular Pharmacology & Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.
Cancer Biology and Genetics Program, The Center for Cell Engineering, The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA; Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY 10065, USA.
Cell Rep. 2017 Nov 21;21(8):2058-2065. doi: 10.1016/j.celrep.2017.10.098.
We discovered that induced pluripotent stem cell (iPSC) clones generated from aged tissue donors (A-iPSCs) fail to suppress oxidative phosphorylation. Compared to embryonic stem cells (ESCs) and iPSCs generated from young donors (Y-iPSCs), A-iPSCs show poor expression of the pluripotent stem cell-specific glucose transporter 3 (GLUT3) and impaired glucose uptake, making them unable to support the high glucose demands of glycolysis. Persistent oxidative phosphorylation in A-iPSCs generates higher levels of reactive oxygen species (ROS), which leads to excessive elevation of glutathione (a ROS-scavenging metabolite) and a blunted DNA damage response. These phenotypes were recapitulated in Y-iPSCs by inhibiting pyruvate dehydrogenase kinase (PDK) or supplying citrate to activate oxidative phosphorylation. In addition, oxidative phosphorylation in A-iPSC clones depletes citrate, a nuclear source of acetyl group donors for histone acetylation; this consequently alters histone acetylation status. Expression of GLUT3 in A-iPSCs recovers the metabolic defect, DNA damage response, and histone acetylation status.
我们发现，源自老年组织供体的诱导多能干细胞（iPSC）克隆无法抑制氧化磷酸化。与胚胎干细胞（ESC）和源自年轻供体的 iPSC（Y-iPSC）相比，A-iPSC 表现出葡萄糖转运蛋白 3（GLUT3）的多能干细胞特异性表达较差，且葡萄糖摄取受损，使其无法支持糖酵解的高葡萄糖需求。A-iPSC 中持续的氧化磷酸化会产生更高水平的活性氧（ROS），导致谷胱甘肽（一种 ROS 清除代谢物）过度升高和 DNA 损伤反应减弱。通过抑制丙酮酸脱氢酶激酶（PDK）或供应柠檬酸来激活氧化磷酸化，可在 Y-iPSC 中重现这些表型。此外，A-iPSC 克隆中的氧化磷酸化会消耗柠檬酸，柠檬酸是组蛋白乙酰化的核来源乙酰基供体；这会导致组蛋白乙酰化状态发生改变。A-iPSC 中 GLUT3 的表达可恢复代谢缺陷、DNA 损伤反应和组蛋白乙酰化状态。
