Biological Significance of the Suppression of Oxidative Phosphorylation in Induced Pluripotent Stem Cells

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. Zhang et al. demonstrate that GLUT3 suppresses somatic cell-specific oxidative phosphorylation in pluripotent stem cells. Low GLUT3 results in higher glutathione, blunting the DNA damage response, and citrate depletion, reducing histone acetylation. Expression of GLUT3 restores regulation.