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Review
. 2019 May 7;20(9):2254.
doi: 10.3390/ijms20092254.

Mechanisms of the Metabolic Shift during Somatic Cell Reprogramming

Ken Nishimura  1 , Aya Fukuda  2 , Koji Hisatake  3
Affiliations
Review

Mechanisms of the Metabolic Shift during Somatic Cell Reprogramming

Ken Nishimura et al. Int J Mol Sci. .

Abstract

Pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), hold a huge promise for regenerative medicine, drug development, and disease modeling. PSCs have unique metabolic features that are akin to those of cancer cells, in which glycolysis predominates to produce energy as well as building blocks for cellular components. Recent studies indicate that the unique metabolism in PSCs is not a mere consequence of their preference for a low oxygen environment, but is an active process for maintaining self-renewal and pluripotency, possibly in preparation for rapid response to the metabolic demands of differentiation. Understanding the regulatory mechanisms of this unique metabolism in PSCs is essential for proper derivation, generation, and maintenance of PSCs. In this review, we discuss the metabolic features of PSCs and describe the current understanding of the mechanisms of the metabolic shift during reprogramming from somatic cells to iPSCs, in which the metabolism switches from oxidative phosphorylation (OxPhos) to glycolysis.

Keywords: ESC; OxPhos: glycolysis; PSC; hypoxia; iPSC; metabolism; mitochondrion; somatic cell reprogramming.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Outline of the glycolytic pathway and TCA cycle. The cell uses glucose transporter, GLUT1, to take up glucose, which is metabolized ultimately to pyruvate in the glycolytic pathway, producing 2 ATP molecules per one glucose molecule. In pluripotent stem cells (PSCs), a majority of glucose-derived pyruvate is converted to lactate and secreted out of the cell while some of pyruvate is transported into mitochondria and converted into acetyl-coenzyme A (acetyl-CoA). The pathways that are connected with the glycolytic pathway produce ribose, nicotinamide adenine dinucleotide (NADPH), and amino acids, which are required for rapidly proliferating cells such as PSCs and cancer cells. In mitochondria, acetyl-CoA is converted into citrate, which, in addition to oxidization in the TCA cycle, will be transported out of the mitochondria into the cytosol and converted back into acetyl-CoA. The cytosolic acetyl-CoA is important for reactions such as lipid synthesis and histone acetylation. Key enzymes that are regulated in the glycolytic pathway are indicated in red. Arrows indicate the flow of metabolites, and the T bar indicated negative regulation of PDH by PDHK1.
Figure 2
Figure 2
Mechanisms of mitochondrial changes during reprogramming. Mitochondria contribute to the hyper-energetic metabolism that generates reactive oxygen species (ROS) at an early stage or reprogramming. The generated ROS serve as a signal to activate nuclear factor (erythroid-derived 2)-like-2 (NRF2), which then induces HIFs. Mitochondria also undergo fission, autophagy (mitophagy) as well as functional inhibition, ultimately becoming less active in producing ATP.
Figure 3
Figure 3
Regulation of glycolysis by AKT. Phosphoinsitide 3-kinase (PI3K) associated with a receptor, such as a receptor tyrosine kinase, phosphorylates phosphatidylinositol (4,5)-bisphosphate (PIP2) to generate phosphatidylinositol (3,4,5)-triphosphate (PIP3). PIP3 then binds and activates 3-Phosphoinositide-dependent protein kinase-1 (PDK1), which then activates AKT by phosphorylation. The phosphorylated AKT elicits activation of the mTOR complex, which leads to higher glycolysis. Leukemia/lymphoma 1 (TCL1) binds to AKT directly and promotes phosphorylation of AKT.
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References

    1. Evans M.J., Kaufman M.H. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292:154–156. doi: 10.1038/292154a0. - DOI - PubMed
    1. Martin G.R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl. Acad. Sci. USA. 1981;78:7634–7638. doi: 10.1073/pnas.78.12.7634. - DOI - PMC - PubMed
    1. Thomson J.A., Itskovitz-Eldor J., Shapiro S.S., Waknitz M.A., Swiergiel J.J., Marshall V.S., Jones J.M. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:1145–1147. doi: 10.1126/science.282.5391.1145. - DOI - PubMed
    1. Takahashi K., Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–676. doi: 10.1016/j.cell.2006.07.024. - DOI - PubMed
    1. Takahashi K., Yamanaka S. A decade of transcription factor-mediated reprogramming to pluripotency. Nat. Rev. Mol. Cell Biol. 2016;17:183–193. doi: 10.1038/nrm.2016.8. - DOI - PubMed

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