title: Metabolome and metaboproteome remodeling in nuclear reprogramming.
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.
authors.affiliation: Center for Regenerative Medicine and Marriott Heart Disease Research Program; Division of Cardiovascular Diseases; Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics; Mayo Clinic; Rochester, MN USA.
authors.forename: Clifford Dl
authors.initials: CD
authors.lastname: Folmes
authors.forename: D Kent
authors.initials: DK
authors.lastname: Arrell
authors.forename: Jelena
authors.initials: J
authors.lastname: Zlatkovic-Lindor
authors.forename: Almudena
authors.initials: A
authors.lastname: Martinez-Fernandez
authors.forename: Carmen
authors.initials: C
authors.lastname: Perez-Terzic
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Nelson
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000648:ultrastructure; D055442:Metabolome; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D060066:Protein Interaction Maps; D020543:Proteome / Q000378:metabolism*
chemical_list: D020543:Proteome
keywords: energy metabolism; glycolysis; iPS cells; mitochondria; network biology; oxidative phosphorylation; proteomics; regenerative medicine; systems biology