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A reduction in ATP demand and mitochondrial activity with neural differentiation of human embryonic stem cells.

TitleA reduction in ATP demand and mitochondrial activity with neural differentiation of human embryonic stem cells.
Publication TypeJournal Article
Year of Publication2011
AuthorsBirket MJ, Orr AL, Gerencser AA, Madden DT, Vitelli C, Swistowski A, Brand MD, Zeng X
JournalJ Cell Sci
Volume124
IssuePt 3
Pagination348-58
Date Published2011 Feb 01
ISSN1477-9137
KeywordsAdaptor Proteins, Signal Transducing, Adenosine Triphosphate, Carrier Proteins, Cell Differentiation, Cell Proliferation, Culture Media, Conditioned, Embryonic Stem Cells, Energy Metabolism, Heat-Shock Proteins, Humans, Mitochondria, Neural Stem Cells, Nuclear Proteins, Oxidative Phosphorylation, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Transcription Factors
Abstract

Here, we have investigated mitochondrial biology and energy metabolism in human embryonic stem cells (hESCs) and hESC-derived neural stem cells (NSCs). Although stem cells collectively in vivo might be expected to rely primarily on anaerobic glycolysis for ATP supply, to minimise production of reactive oxygen species, we show that in vitro this is not so: hESCs generate an estimated 77% of their ATP through oxidative phosphorylation. Upon differentiation of hESCs into NSCs, oxidative phosphorylation declines both in absolute rate and in importance relative to glycolysis. A bias towards ATP supply from oxidative phosphorylation in hESCs is consistent with the expression levels of the mitochondrial gene regulators peroxisome-proliferator-activated receptor γ coactivator (PGC)-1α, PGC-1β and receptor-interacting protein 140 (RIP140) in hESCs when compared with a panel of differentiated cell types. Analysis of the ATP demand showed that the slower ATP turnover in NSCs was associated with a slower rate of most energy-demanding processes but occurred without a reduction in the cellular growth rate. This mismatch is probably explained by a higher rate of macromolecule secretion in hESCs, on the basis of evidence from electron microscopy and an analysis of conditioned media. Taken together, our developmental model provides an understanding of the metabolic transition from hESCs to more quiescent somatic cell types, and supports important roles for mitochondria and secretion in hESC biology.

DOI10.1242/jcs.072272
Alternate JournalJ. Cell. Sci.
PubMed ID21242311
PubMed Central IDPMC3021997
Grant ListPL1 AG032118 / AG / NIA NIH HHS / United States
P01 AG025901 / AG / NIA NIH HHS / United States
R01 AG033542-02 / AG / NIA NIH HHS / United States
R01 AG033542 / AG / NIA NIH HHS / United States
P30 AG025708 / AG / NIA NIH HHS / United States