A feed-forward Ca2+-dependent mechanism boosting glycolysis and OXPHOS by activating Aralar-malate-aspartate shuttle, upon neuronal stimulation

Perez-Liebana, I.; Juaristi, I.; Gonzalez-Sanchez, P.; Gonzalez-Moreno, L.; Rial, E.; Podunavac, M.; Zakarian, A.; Molgo, J.; Pardo, B.; Satrustegui, J.; del Arco, A.

doi:10.1101/2021.02.02.429391

bioRxiv · 10.1101/2021.02.02.429391

A feed-forward Ca2+-dependent mechanism boosting glycolysis and OXPHOS by activating Aralar-malate-aspartate shuttle, upon neuronal stimulation

Perez-Liebana, I.·Juaristi, I.·Gonzalez-Sanchez, P.·Gonzalez-Moreno, L.·Rial, E.·Podunavac, M.·Zakarian, A.·Molgo, J.·Pardo, B.·Satrustegui, J.·del Arco, A.

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Abstract

Calcium is an important second messenger regulating a bioenergetic response to the workloads triggered by neuronal activation. In cortical neurons using glucose as only fuel, activation by NMDA, which elicits a strong workload dependent on Na+ entry, stimulates glucose uptake, glycolysis, pyruvate and lactate production, and OXPHOS in a Ca2+-dependent way. We find that Ca2+-upregulation of glycolysis, pyruvate levels and respiration, but not glucose uptake, all depend on Aralar/AGC1/Slc25a12, the Ca2+regulated mitochondrial aspartate-glutamate carrier, component of the malate-aspartate shuttle (MAS). Ca2+-activation of MAS increases pyruvate production, which directly fuels workload-stimulated respiration. Also it stimulates glycolysis. MCU silencing had no effect indicating that none of these processes required mitochondrial Ca2+. The neuronal respiratory response to carbachol was also dependent on Aralar, but not on MCU. We also find that cortical neurons are endowed with a constitutive ER-to-mitochondria Ca2+ flow maintaining basal cell bioenergetics in which Ryanodine receptors, RyR2, rather than InsP3R, are responsible for Ca2+ release, and in which MCU does not participate. The results reveal that in neurons using glucose MCU does not participate in OXPHOS regulation under basal or stimulated conditions, while Aralar-MAS appears as the major Ca2+-dependent pathway tuning simultaneously glycolysis and OXPHOS to neuronal activation.

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Perez-Liebana, I., Juaristi, I., Gonzalez-Sanchez, P., Gonzalez-Moreno, L., Rial, E., Podunavac, M., Zakarian, A., Molgo, J., Pardo, B., Satrustegui, J., del Arco, A.. 2021-02-03. A feed-forward Ca2+-dependent mechanism boosting glycolysis and OXPHOS by activating Aralar-malate-aspartate shuttle, upon neuronal stimulation. https://doi.org/10.1101/2021.02.02.429391

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