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Determinants of Brain Cell Metabolic Phenotypes and Energy Substrate Utilization Unraveled with a Modeling Approach
Figure 2
Jshuttle and vmax,PDH determine the occurrence of oxidative vs. glycolytic phenotype.
(A) Oxidative phenotype: In the basal state (black), both lactate transport and glycolysis contribute to JPDH (43% and 57% respectively [29]). We show the resulting steady state transport, glycolytic and JPDH fluxes upon stimulation (very dark gray “ctrl-bar": +30% vmax,PDH, +30% kshuttle, +48.5% vmax,glyco; dark gray: +80% vmax,MCT,, +30% vmax,PDH, +30% kshuttle, +48.5% vmax,glyco; light gray: +80% Le, +30% vmax,PDH, +30% kshuttle, +48.5% Jmax,glyco; white: +80% vmax,MCT, +80% Le, +30% vmax,PDH, +30% kshuttle, +48.5% vmax,glyco). (B) Glycolytic phenotype: In the basal state (black), parameters have been chosen such that lactate is taken out of the cell (
, 
). We show the resulting steady state transport, glycolytic and JPDH fluxes upon stimulation (very dark gray “ctrl-bar": +30% vmax,PDH, +30% kshuttle, +48.5% vmax,glyco; dark gray: +80% vmax,MCT, +15% vmax,PDH, +0% kshuttle, +48.5% vmax,glyco; light gray: +80% Le, +15% vmax,PDH, +0% kshuttle, +48.5% vmax,glyco; white: +80% Le, +80% vmax,MCT, +15% vmax,PDH, +0% kshuttle, +48.5% vmax,glyco). See Description of the model for equations and Choice of parameters for parameters. (C–D) Basal lactate transport (C) and oxidative metabolism (D) when varying vmax,PDH and kshuttle. We considered 20 different values evenly spaced in the range 
and 
, resulting in 400 simulations. For each simulation, we recorded the steady state value of JMCT and JPDH. We show the resulting iso-curves (note that vmax,PDH and kshuttle were normalized to their basal oxidative value, so that (1,1) (marked by ‘o’) corresponds to the parameters used in Fig. 2A and (0.2,0.3) (marked by ‘g’) corresponds to the parameters used in Fig. 2B). In non-shaded regions, the ratio 
[32], 
and 
[34].
doi: https://doi.org/10.1371/journal.pcbi.1002686.g002