9
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism

      review-article
      The Journal of Cell Biology
      Rockefeller University Press

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Yellen reviews how cellular metabolism responds acutely to the intense energy requirements of neurons when they are stimulated.

          Abstract

          The brain’s energy demands are remarkable both in their intensity and in their moment-to-moment dynamic range. This perspective considers the evidence for Warburg-like aerobic glycolysis during the transient metabolic response of the brain to acute activation, and it particularly addresses the cellular mechanisms that underlie this metabolic response. The temporary uncoupling between glycolysis and oxidative phosphorylation led to the proposal of an astrocyte-to-neuron lactate shuttle whereby during stimulation, lactate produced by increased glycolysis in astrocytes is taken up by neurons as their primary energy source. However, direct evidence for this idea is lacking, and evidence rather supports that neurons have the capacity to increase their own glycolysis in response to stimulation; furthermore, neurons may export rather than import lactate in response to stimulation. The possible cellular mechanisms for invoking metabolic resupply of energy in neurons are also discussed, in particular the roles of feedback signaling via adenosine diphosphate and feedforward signaling by calcium ions.

          Related collections

          Most cited references99

          • Record: found
          • Abstract: found
          • Article: not found

          Pyruvate kinase M2 is a phosphotyrosine-binding protein.

          Growth factors stimulate cells to take up excess nutrients and to use them for anabolic processes. The biochemical mechanism by which this is accomplished is not fully understood but it is initiated by phosphorylation of signalling proteins on tyrosine residues. Using a novel proteomic screen for phosphotyrosine-binding proteins, we have made the observation that an enzyme involved in glycolysis, the human M2 (fetal) isoform of pyruvate kinase (PKM2), binds directly and selectively to tyrosine-phosphorylated peptides. We show that binding of phosphotyrosine peptides to PKM2 results in release of the allosteric activator fructose-1,6-bisphosphate, leading to inhibition of PKM2 enzymatic activity. We also provide evidence that this regulation of PKM2 by phosphotyrosine signalling diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors. Collectively, our results indicate that expression of this phosphotyrosine-binding form of pyruvate kinase is critical for rapid growth in cancer cells.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Myelination and support of axonal integrity by glia.

            The myelination of axons by glial cells was the last major step in the evolution of cells in the vertebrate nervous system, and white-matter tracts are key to the architecture of the mammalian brain. Cell biology and mouse genetics have provided insight into axon-glia signalling and the molecular architecture of the myelin sheath. Glial cells that myelinate axons were found to have a dual role by also supporting the long-term integrity of those axons. This function may be independent of myelin itself. Myelin abnormalities cause a number of neurological diseases, and may also contribute to complex neuropsychiatric disorders.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1.

              Neurons are known to have a lower glycolytic rate than astrocytes and when stressed they are unable to upregulate glycolysis because of low Pfkfb3 (6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase-3) activity. This enzyme generates fructose-2,6-bisphosphate (F2,6P(2)), the most potent activator of 6-phosphofructo-1-kinase (Pfk1; ref. 4), a master regulator of glycolysis. Here, we show that Pfkfb3 is absent from neurons in the brain cortex and that Pfkfb3 in neurons is constantly subject to proteasomal degradation by the action of the E3 ubiquitin ligase, anaphase-promoting complex/cyclosome (APC/C)-Cdh1. By contrast, astrocytes have low APC/C-Cdh1 activity and therefore Pfkfb3 is present in these cells. Upregulation of Pfkfb3 by either inhibition of Cdh1 or overexpression of Pfkfb3 in neurons resulted in the activation of glycolysis. This, however, was accompanied by a marked decrease in the oxidation of glucose through the pentose phosphate pathway (a metabolic route involved in the regeneration of reduced glutathione) resulting in oxidative stress and apoptotic death. Thus, by actively downregulating glycolysis by APC/C-Cdh1, neurons use glucose to maintain their antioxidant status at the expense of its utilization for bioenergetic purposes.
                Bookmark

                Author and article information

                Journal
                J Cell Biol
                J. Cell Biol
                jcb
                jcb
                The Journal of Cell Biology
                Rockefeller University Press
                0021-9525
                1540-8140
                02 July 2018
                : 217
                : 7
                : 2235-2246
                Affiliations
                [1]Department of Neurobiology, Harvard Medical School, Boston, MA
                Author notes
                Correspondence to Gary Yellen: gary_yellen@hms.harvard.edu
                Author information
                http://orcid.org/0000-0003-4228-7866
                Article
                201803152
                10.1083/jcb.201803152
                6028533
                29752396
                b1d68fe2-08d1-4913-b1e7-4fd6f4616374
                © 2018 Yellen

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 26 March 2018
                : 30 April 2018
                : 02 May 2018
                Funding
                Funded by: National Institutes of Health, DOI https://doi.org/10.13039/100000002;
                Award ID: R01 NS055031
                Award ID: DP1 EB016985
                Award ID: R01 NS102586
                Award ID: R01 GM124038
                Categories
                Reviews
                Perspective
                29
                43
                41

                Cell biology
                Cell biology

                Comments

                Comment on this article