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Astrocytes and neurons communicate via a monocarboxylic acid shuttle

1 Ruhr Universität Bochum, LWL-Hospital of Psychiatry, Bochum, Germany
2 School of Pharmacy, University of Reading, Reading, RG6 6AP, UK

Topical Section: Neuroscience Techniques/Applied Neuroscience

Since formulation of the Astrocyte-Neuron Lactate Shuttle (ANLS) hypothesis in 1994, the hypothesis has provoked criticism and debate. Our review does not criticise, but rather integrates experimental data characterizing proton-linked monocarboxylate transporters (MCTs) into the ANLS. MCTs have wide substrate specificity and are discussed to be in protein complex with a proton donor (PD). We particularly focus on the proton-driven transfer of L -lactic acid ( L -lacH) and pyruvic acid (pyrH), were PDs link MCTs to a flow of energy. The precise nature of the PD predicts the activity and catalytic direction of MCTs. By doing so, we postulate that the MCT4ꞏphosphoglycerate kinase complex exports and at the same time in the same astrocyte, MCT1ꞏcarbonic anhydrase II complex imports monocarboxylic acids. Similarly, neuronal MCT2 preferentially imports pyrH. The repertoire of MCTs in astrocytes and neurons allows them to communicate via monocarboxylic acids. A change in imported pyrH/ L -lacH ratio in favour of L -lacH encodes signals stabilizing the transit of glucose from astrocytes to neurons. The presented astrocyte neuron communication hypothesis has the potential to unite the community by suggesting that the exchange of monocarboxylic acids paves the path of glucose provision.
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Keywords astrocyte neuron glucose transit; astrocyte neuron lactate shuttle; enzyme complexes

Citation: Dirk Roosterman, Graeme S. Cottrell. Astrocytes and neurons communicate via a monocarboxylic acid shuttle. AIMS Neuroscience, 2020, 7(2): 94-106. doi: 10.3934/Neuroscience.2020007

References

  • 1. Pellerin L, Magistretti PJ (2003) Food for thought: challenging the dogmas. J Cereb Blood Flow Metab 23: 1282–1286.    
  • 2. Pellerin L, Magistretti PJ (1994) Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci U S A 91: 10625–10629.    
  • 3. Simpson IA, Carruthers A, Vannucci SJ (2007) Supply and demand in cerebral energy metabolism: the role of nutrient transporters. J Cereb Blood Flow Metab 27: 1766–1791.    
  • 4. Prigogine I (1978) Time, structure, and fluctuations. Science (New York, NY) 201: 777–785.    
  • 5. Morowitz HJ (1992) Beginnings of Cellular Life: Metabolism Recapitulates Biogenesis: Yale University Press.
  • 6. Jørgensen SE (1999) Tentative fourth law of thermodynamics, applied to description of ecosystem development. Ann N Y Acad Sci 879: 320–343.    
  • 7. Roosterman D, Meyerhof W, Cottrell GS (2018) Proton transport chains in glucose metabolism: mind the proton. Front Neurosci 12: 404.    
  • 8. Crane RK, Krane SM (1956) On the mechanism of the intestinal absorption of sugars. Biochim Biophys Acta 20: 568–569.    
  • 9. Hamilton KL (2013) Robert K. Crane-Na+-glucose cotransporter to cure? Front Physiol 4: 53.
  • 10. Hebb DO (1949) The Organization of Behavior: A Neuropsychological Theory: Wiley, 368.
  • 11. Ho M-W, Ulanowicz R (2005) Sustainable systems as organisms? Biosystems 82: 39–51.    
  • 12. Bonen A (2001) The expression of lactate transporters (MCT1 and MCT4) in heart and muscle. Eur J Appl Physiol 86: 6–11.    
  • 13. Halestrap AP (2013) Monocarboxylic acid transport. Compr Physiol 3: 1611–1643.
  • 14. Van Hee VF, Labar D, Dehon G, et al. (2017) Radiosynthesis and validation of (+/−)-[18F]-3-fluoro-2-hydroxypropionate ([18F]-FLac) as a PET tracer of lactate to monitor MCT1- dependent lactate uptake in tumors. Oncotarget 8: 24415–24428.
  • 15. Pullen TJ, Sylow L, Sun G, et al. (2012) Overexpression of monocarboxylate transporter-1 (SLC16A1) in mouse pancreatic β-cells leads to relative hyperinsulinism during exercise. Diabetes 61: 1719–1725.    
  • 16. Becker HM, Klier M, Schüler C, et al. (2011) Intramolecular proton shuttle supports not only catalytic but also noncatalytic function of carbonic anhydrase II. Proc Natl Acad Sci U S A 108: 3071–3076.    
  • 17. Noor SI, Dietz S, Heidtmann H, et al. (2015) Analysis of the binding moiety mediating the interaction between monocarboxylate transporters and carbonic anhydrase II. J Biol Chem 290: 4476–4486.    
  • 18. Noor SI, Jamali S, Ames S, et al. (2018) A surface proton antenna in carbonic anhydrase II supports lactate transport in cancer cells. Elife 7: e35176.    
  • 19. Dimmer KS, Friedrich B, Lang F, et al. (2000) The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem J 350: 219–227.    
  • 20. Lynch CJ, Xu Y, Hajnal A, et al. (2015) RNA sequencing reveals a slow to fast muscle fiber type transition after olanzapine infusion in rats. PloS One 10: e0123966.    
  • 21. Pierre K, Magistretti PJ, Pellerin L (2002) MCT2 is a major neuronal monocarboxylate transporter in the adult mouse brain. J Cereb Blood Flow Metab 22: 586–595.    
  • 22. Forero-Quintero LS, Ames S, Schneider H-P, et al. (2019) Membrane-anchored carbonic anhydrase IV interacts with monocarboxylate transporters via their chaperones CD147 and GP70. J Biol Chem 294: 593–607.    
  • 23. Klier M, Schüler C, Halestrap AP, et al. (2011) Transport activity of the high-affinity monocarboxylate transporter MCT2 is enhanced by extracellular carbonic anhydrase IV but not by intracellular carbonic anhydrase II. J Biol Chem 286: 27781–27791.    
  • 24. Itel F, Al-Samir S, Öberg F, et al. (2012) CO2 permeability of cell membranes is regulated by membrane cholesterol and protein gas channels. FASEB J 26: 5182–5191.    
  • 25. Cornelius F (2001) Modulation of Na,K-ATPase and Na-ATPase activity by phospholipids and cholesterol. I. Steady-state kinetics. Biochemistry 40: 8842–8851.
  • 26. Broer S, Broer A, Schneider HP, et al. (1999) Characterization of the high-affinity monocarboxylate transporter MCT2 in Xenopus laevis oocytes. Biochem J 341: 529–535.    
  • 27. Lin RY, Vera JC, Chaganti RS, et al. (1998) Human monocarboxylate transporter 2 (MCT2) is a high affinity pyruvate transporter. J Biol Chem 273: 28959–28965.    
  • 28. Gibbs ME (2015) Role of glycogenolysis in memory and learning: regulation by noradrenaline, serotonin and ATP. Front Integr Neurosci 9: 70.
  • 29. Magistretti PJ, Allaman I (2015) A cellular perspective on brain energy metabolism and functional imaging. Neuron 86: 883–901.    
  • 30. Newman LA, Korol DL, Gold PE (2011) Lactate produced by glycogenolysis in astrocytes regulates memory processing. PloS One 6: e28427.    
  • 31. Suzuki A, Stern SA, Bozdagi O, et al. (2011) Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144: 810–823.    
  • 32. Bröer S, Schneider HP, Bröer A, et al. (1998) Characterization of the monocarboxylate transporter 1 expressed in Xenopus laevis oocytes by changes in cytosolic pH. Biochem J 333: 167–174.    
  • 33. de Bruijne AW, Vreeburg H, van Steveninck J (1985) Alternative-substrate inhibition of L-lactate transport via the monocarboxylate-specific carrier system in human erythrocytes. Biochim Biophys Acta 812: 841–844.    
  • 34. Sahlin K, Harris RC, Nylind B, et al. (1976) Lactate content and pH in muscle obtained after dynamic exercise. Pflugers Arch 367: 143–149.    
  • 35. Urbańska K, Orzechowski A (2019) Unappreciated role of LDHA and LDHB to control apoptosis and autophagy in tumor cells. Int J Mol Sci 20: E2085.    
  • 36. Svedružić ŽM, Odorčić I, Chang CH, et al. (2020) Substrate channeling via a transient protein-protein complex: the case of D-Glyceraldehyde-3-Phosphate dehydrogenase and L-Lactate dehydrogenase. bioRxiv: 2020.2001.2022.916023.
  • 37. Svedruzić ZM, Spivey HO (2006) Interaction between mammalian glyceraldehyde-3-phosphate dehydrogenase and L-lactate dehydrogenase from heart and muscle. Proteins 63: 501–511.    
  • 38. Ovádi J, Srere PA (1992) Channel your energies. Trends Biochem Sci 17: 445–447.    
  • 39. Reed CA (2013) Myths about the proton. The nature of H+ in condensed media. Acc Chem Res 46: 2567–2575.
  • 40. Hashimoto T, Hussien R, Brooks GA (2006) Colocalization of MCT1, CD147, and LDH in mitochondrial inner membrane of L6 muscle cells: evidence of a mitochondrial lactate oxidation complex. Am J Physiol Endocrinol Metab 290: E1237–1244.    
  • 41. Fredriksson S, Gullberg M, Jarvius J, et al. (2002) Protein detection using proximity-dependent DNA ligation assays. Nat Biotechnol 20: 473–477.    
  • 42. Soderberg O, Leuchowius KJ, Gullberg M, et al. (2008) Characterizing proteins and their interactions in cells and tissues using the in situ proximity ligation assay. Methods 45: 227–232.    
  • 43. Brooks GA (2020) Lactate as a fulcrum of metabolism. Redox Biol, 101454.
  • 44. Tadi M, Allaman I, Lengacher S, et al. (2015) Learning-Induced gene expression in the hippocampus reveals a role of neuron -astrocyte metabolic coupling in long term memory. PloS One 10: e0141568.    
  • 45. Contreras-Baeza Y, Sandoval PY, Alarcón R, et al. (2019) Monocarboxylate transporter 4 (MCT4) is a high affinity transporter capable of exporting lactate in high-lactate microenvironments. J Biol Chem 294: 20135–20147.    
  • 46. Takanaga H, Chaudhuri B, Frommer WB (2008) GLUT1 and GLUT9 as major contributors to glucose influx in HepG2 cells identified by a high sensitivity intramolecular FRET glucose sensor. Biochim Biophys Acta 1778: 1091–1099.    
  • 47. Nedergaard M, Ransom B, Goldman SA (2003) New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci 26: 523–530.    
  • 48. Korogod N, Petersen CCH, Knott GW (2015) Ultrastructural analysis of adult mouse neocortex comparing aldehyde perfusion with cryo fixation. Elife 4.
  • 49. Mason S (2017) Lactate shuttles in neuroenergetics-homeostasis, allostasis and beyond. Front Neurosci 11: 43.
  • 50. Pellerin L (2010) Food for thought: the importance of glucose and other energy substrates for sustaining brain function under varying levels of activity. Diabetes Metab 36: S59–63.    
  • 51. Gandhi GK, Cruz NF, Ball KK, et al. (2009) Astrocytes are poised for lactate trafficking and release from activated brain and for supply of glucose to neurons. J Neurochem 111: 522–536.    
  • 52. Iliff J, Simon M (2019) CrossTalk proposal: The glymphatic system supports convective exchange of cerebrospinal fluid and brain interstitial fluid that is mediated by perivascular aquaporin-4. J Physiol 597: 4417–4419.    
  • 53. Leen WG, Willemsen MA, Wevers RA, et al. (2012) Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice. PloS One 7: e42745.    
  • 54. Gjedden A, Hansen A, Silver I (1980) The glucose concentration of brain interstitial fluid is low. Proc Int Union Physiol Sci 14.
  • 55. Prats C, Graham TE, Shearer J (2018) The dynamic life of the glycogen granule. J Biol Chem 293: 7089–7098.    
  • 56. Lowry OH, Passonneau JV, Hasselberger FX, et al. (1964) Effect of ischemia on known substrates and cofactors of the glycolytic pathway in brain. J Biol Chem 239: 18–30.
  • 57. Scemes E, Giaume C (2006) Astrocyte calcium waves: what they are and what they do. Glia 54: 716–725.    

 

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