%0 Journal Article %A Connolly, Niamh MC %A D'Orsi, Beatrice %A Monsefi, Naser %A Huber, Heinrich J. %A Prehn, Jochen HM %D 2019 %T Computational Analysis of AMPK-Mediated Neuroprotection Suggests Acute Excitotoxic Bioenergetics and Glucose Dynamics Are Regulated by a Minimal Set of Critical Reactions. %U https://repository.rcsi.com/articles/journal_contribution/Computational_Analysis_of_AMPK-Mediated_Neuroprotection_Suggests_Acute_Excitotoxic_Bioenergetics_and_Glucose_Dynamics_Are_Regulated_by_a_Minimal_Set_of_Critical_Reactions_/10793120 %2 https://repository.rcsi.com/ndownloader/files/19305293 %K Bioenergy %K calcium cell level %K calcium transport %K cell stress %K controlled study %K enzyme activity %K glucose transport %K mathematical model %K neuroprotection %K sensitivity analysis. %K Physiology %K Medical Physics %X

Loss of ionic homeostasis during excitotoxic stress depletes ATP levels and activates the AMP-activated protein kinase (AMPK), re-establishing energy production by increased expression of glucose transporters on the plasma membrane. Here, we develop a computational model to test whether this AMPK-mediated glucose import can rapidly restore ATP levels following a transient excitotoxic insult. We demonstrate that a highly compact model, comprising a minimal set of critical reactions, can closely resemble the rapid dynamics and cell-to-cell heterogeneity of ATP levels and AMPK activity, as confirmed by single-cell fluorescence microscopy in rat primary cerebellar neurons exposed to glutamate excitotoxicity. The model further correctly predicted an excitotoxicity-induced elevation of intracellular glucose, and well resembled the delayed recovery and cell-to-cell heterogeneity of experimentally measured glucose dynamics. The model also predicted necrotic bioenergetic collapse and altered calcium dynamics following more severe excitotoxic insults. In conclusion, our data suggest that a minimal set of critical reactions may determine the acute bioenergetic response to transient excitotoxicity and that an AMPK-mediated increase in intracellular glucose may be sufficient to rapidly recover ATP levels following an excitotoxic insult.

%I Royal College of Surgeons in Ireland