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Metabolic differentiation in the embryonic retina

Nature Cell Biology volume 14, pages 859–864 (2012)Cite this article

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Abstract

Unlike healthy adult tissues, cancers produce energy mainly by aerobic glycolysis instead of oxidative phosphorylation1. This adaptation, called the Warburg effect, may be a feature of all dividing cells, both normal and cancerous2, or it may be specific to cancers3. It is not known whether, in a normally growing tissue during development, proliferating and postmitotic cells produce energy in fundamentally different ways. Here we show in the embryonic Xenopus retina in vivo, that dividing progenitor cells depend less on oxidative phosphorylation for ATP production than non-dividing differentiated cells, and instead use glycogen to fuel aerobic glycolysis. The transition from glycolysis to oxidative phosphorylation is connected to the cell differentiation process. Glycolysis is indispensable for progenitor proliferation and biosynthesis, even when it is not used for ATP production. These results suggest that the Warburg effect can be a feature of normal proliferation in vivo, and that the regulation of glycolysis and oxidative phosphorylation is critical for normal development.

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Figure 1: Proliferating cells rely less than differentiated cells on oxidative phosphorylation for ATP, and have higher levels of glycolysis.
Figure 2: Metabolic differences between progenitors and differentiated cells are also present in the postembryonic retinal stem cell niche, and in the zebrafish retina.
Figure 3: Inhibition of glycogen breakdown shifts energy production from glycolysis to oxidative phosphorylation.
Figure 4: Cell differentiation can affect energy metabolism, whereas shifting energy metabolism to oxidative phosphorylation does not influence aspects of proliferation and differentiation.
Figure 5: Complete glycolytic block inhibits progenitor proliferation, biosynthesis and survival.

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Acknowledgements

We are grateful to F. Gallagher and H. Sladen for help with the LDH assays, N. Miller for cell sorting and D. Attwell for advice on the oxygen concentration measurements. We thank J. Bixby, C. Holt, S. Morrison, S. He and R. Johnson for comments on the manuscript. We thank the Wellcome Trust (W.A.H.) and Gonville and Caius College and the Royal Commission for the Exhibition of 1851 (M.A.) for financial support.

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Author notes

  1. Michalis Agathocleous

    Present address: Present addresses: Children’s Research Institute, UT Southwestern, Dallas, Texas 75390, USA (M.A.); Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA (O.R.),

Authors and Affiliations

  1. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK

    Michalis Agathocleous, Nicola K. Love, Owen Randlett, Jinyue Liu, Andrew J. Murray & William A. Harris

  2. Gonville and Caius College, Cambridge CB2 1TA, UK

    Michalis Agathocleous

  3. Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK

    Julia J. Harris

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Contributions

M.A. conceived the study, carried out most of the experiments and co-wrote the paper. N.K.L. did the LDH and lactate assays and helped with several other aspects of the experimental work. O.R. did the Eb3–GFP imaging in zebrafish. J.J.H. did the in vivo oxygen recordings. J.L. did the SDH histochemistry. The oxygen consumption assays were done with A.J.M. W.A.H. guided the research and co-wrote the paper.

Corresponding authors

Correspondence to Michalis Agathocleous or William A. Harris.

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The authors declare no competing financial interests.

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Agathocleous, M., Love, N., Randlett, O. et al. Metabolic differentiation in the embryonic retina. Nat Cell Biol 14, 859–864 (2012). https://doi.org/10.1038/ncb2531

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