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

Cheng Zhang, Maria Skamagki, Zhong Liu, Aparna Ananthanarayanan, Rui Zhao, Hu Li, Kitai Kim

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2058-2065
Number of pages8
JournalCell reports
Volume21
Issue number8
DOIs
StatePublished - Nov 21 2017

Keywords

  • DNA damage response
  • ROS
  • histone acetylation
  • homeostatic balance
  • induced pluripotent stem cells
  • oxidative phosphorylation
  • reactive oxygen species

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Biological Significance of the Suppression of Oxidative Phosphorylation in Induced Pluripotent Stem Cells'. Together they form a unique fingerprint.

Cite this