Metabolome and metaboproteome remodeling in nuclear reprogramming

Clifford Folmes, D. Kent Arrell, Jelena Zlatkovic-Lindor, Almudena Martinez-Fernandez, Carmen M Terzic, Timothy J Nelson, Andre Terzic

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Nuclear reprogramming resets differentiated tissue to generate induced pluripotent stem (iPS) cells. While genomic attributes underlying reacquisition of the embryonic-like state have been delineated, less is known regarding the metabolic dynamics underscoring induction of pluripotency. Metabolomic profiling of fibroblasts vs. iPS cells demonstrated nuclear reprogramming-associated induction of glycolysis, realized through augmented utilization of glucose and accumulation of lactate. Real-time assessment unmasked downregulated mitochondrial reserve capacity and ATP turnover correlating with pluripotent induction. Reduction in oxygen consumption and acceleration of extracellular acidification rates represent high-throughput markers of the transition from oxidative to glycolytic metabolism, characterizing stemness acquisition. The bioenergetic transition was supported by proteome remodeling, whereby 441 proteins were altered between fibroblasts and derived iPS cells. Systems analysis revealed overrepresented canonical pathways and interactome-associated biological processes predicting differential metabolic behavior in response to reprogramming stimuli, including upregulation of glycolysis, purine, arginine, proline, ribonucleoside and ribonucleotide metabolism, and biopolymer and macromolecular catabolism, with concomitant downregulation of oxidative phosphorylation, phosphate metabolism regulation, and precursor biosynthesis processes, prioritizing the impact of energy metabolism within the hierarchy of nuclear reprogramming. Thus, metabolome and metaboproteome remodeling is integral for induction of pluripotency, expanding on the genetic and epigenetic requirements for cell fate manipulation.

Original languageEnglish (US)
Pages (from-to)2355-2365
Number of pages11
JournalCell Cycle
Volume12
Issue number15
DOIs
StatePublished - Aug 1 2013

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Metabolome
Induced Pluripotent Stem Cells
Glycolysis
Energy Metabolism
Down-Regulation
Ribonucleosides
Ribonucleotides
Biological Phenomena
Biopolymers
Metabolomics
Oxidative Phosphorylation
Proteome
Systems Analysis
Proline
Epigenomics
Oxygen Consumption
Arginine
Lactic Acid
Up-Regulation
Fibroblasts

Keywords

  • Energy metabolism
  • Glycolysis
  • IPS cells
  • Mitochondria
  • Network biology
  • Oxidative phosphorylation
  • Proteomics
  • Regenerative medicine
  • Systems biology

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

Metabolome and metaboproteome remodeling in nuclear reprogramming. / Folmes, Clifford; Kent Arrell, D.; Zlatkovic-Lindor, Jelena; Martinez-Fernandez, Almudena; Terzic, Carmen M; Nelson, Timothy J; Terzic, Andre.

In: Cell Cycle, Vol. 12, No. 15, 01.08.2013, p. 2355-2365.

Research output: Contribution to journalArticle

Folmes, C, Kent Arrell, D, Zlatkovic-Lindor, J, Martinez-Fernandez, A, Terzic, CM, Nelson, TJ & Terzic, A 2013, 'Metabolome and metaboproteome remodeling in nuclear reprogramming', Cell Cycle, vol. 12, no. 15, pp. 2355-2365. https://doi.org/10.4161/cc.25509
Folmes C, Kent Arrell D, Zlatkovic-Lindor J, Martinez-Fernandez A, Terzic CM, Nelson TJ et al. Metabolome and metaboproteome remodeling in nuclear reprogramming. Cell Cycle. 2013 Aug 1;12(15):2355-2365. https://doi.org/10.4161/cc.25509
Folmes, Clifford ; Kent Arrell, D. ; Zlatkovic-Lindor, Jelena ; Martinez-Fernandez, Almudena ; Terzic, Carmen M ; Nelson, Timothy J ; Terzic, Andre. / Metabolome and metaboproteome remodeling in nuclear reprogramming. In: Cell Cycle. 2013 ; Vol. 12, No. 15. pp. 2355-2365.
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