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Aerobic Glycolysis in the Brain: Warburg and Crabtree Contra Pasteur

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Abstract

Information processing is onerous. Curiously, active brain tissue does not fully oxidize glucose and instead generates a local surplus of lactate, a phenomenon termed aerobic glycolysis. Why engage in inefficient ATP production by glycolysis when energy demand is highest and oxygen is plentiful? Aerobic glycolysis is associated to classic biochemical effects known by the names of Pasteur, Warburg and Crabtree. Here we discuss these three interdependent phenomena in brain cells, in light of high-resolution data of neuronal and astrocytic metabolism in culture, tissue slices and in vivo, acquired with genetically-encoded fluorescent sensors. These sensors are synthetic proteins that can be targeted to specific cell types and subcellular compartments, which change their fluorescence in response to variations in metabolite concentration. A major site of acute aerobic glycolysis is the astrocyte. In this cell, a Crabtree effect triggered by K+ coincides with a Warburg effect mediated by NO, superimposed on a slower longer-lasting Warburg effect caused by glutamate and possibly by NH4+. The compounded outcome is that more fuel (lactate) and more oxygen are made available to neurons, on demand. Meanwhile neurons consume both glucose and lactate, maintaining a strict balance between glycolysis and respiration, commanded by the Na+ pump. We conclude that activity-dependent Warburg and Crabtree effects in brain tissue, and the resulting aerobic glycolysis, do not reflect inefficient energy generation but the marshalling of astrocytes for the purpose of neuronal ATP generation. It remains to be seen whether neurons contribute to aerobic glycolysis under physiological conditions.

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Acknowledgements

We thank all members of the Barros Lab for their contributions and discussions. We also thank Karen Everett for critical reading of the manuscript. This work was partially funded by CONICYT-BMBF Grant 180045. The Centro de Estudios Científicos (CECs) is funded by the Chilean Government through the Centers of Excellence Basal Financing Program of CONICYT.

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  1. Centro de Estudios Científicos—CECs, 5110466, Valdivia, Chile

    L. Felipe Barros, Iván Ruminot, Alejandro San Martín, Rodrigo Lerchundi, Ignacio Fernández-Moncada & Felipe Baeza-Lehnert

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  1. L. Felipe Barros
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  2. Iván Ruminot
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Barros, L.F., Ruminot, I., San Martín, A. et al. Aerobic Glycolysis in the Brain: Warburg and Crabtree Contra Pasteur. Neurochem Res 46, 15–22 (2021). https://doi.org/10.1007/s11064-020-02964-w

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