Figure 1.
Model describing the simplified energetics of brain cells.
Glucose undergoes glycolysis and all resulting pyruvate is either further metabolized by PDH or converted to lactate by LDH before being transported out of the cell. On the other hand, lactate can be transported into the cell and then metabolized into pyruvate by LDH. Because these processes require NAD+/NADH, we also modeled the “recycling" shuttle of NADH to NAD+ by mitochondria. The red arrow shows the metabolism of a typical predominantly glycolytic cell, characterized by lactate export; the blue arrow shows a typical oxidative phenotype, where both glucose and lactate import contribute to oxidative phosphorylation. Abbreviations: Le, extracellular lactate; Li, intracellular lactate; P, pyruvate; NADH, reduced nicotinamide-adenine dinucleotide; Glc, glucose; JMCT, transmembrane flux of lactate via MCTs; Jshuttle, flux of NADH to NAD+ “recycling" by the mitochondria; Jglyco, glycolytic flux; JLDH, metabolic flux via LDH; JPDH, metabolic flux via PDH.
Table 1.
Importance of lactate transport regulation.
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].
Figure 3.
Importance of lactate transport for oxidative phosphorylation in oxidative cells.
(A) As a starting point, it was assumed that lactate transport and glycolysis contribute 43% and 57%, respectively, to oxidative phosphorylation (r = 0.75 [29]). Lactate transport was then stimulated by increasing vmax,MCT and Le in the range 0–80%. The iso-curves show JPDH normalized to its basal value (as a measure of oxidative phosphorylation). Note that in parallel, vmax,PDH and kshuttle were multiplied by a factor f = 1.3, while the glycolytic flux remained fixed to its basal level. In all regions, the ratio [32] and
[34]. (B) As in (A), but f = 1.7. (C) As in (A), but r = 2.2 [28]. (D) As in (A), but r = 2.2 [28] and f = 1.7. See Description of the model for equations and Choice of parameters for parameters.
Figure 4.
Model validity tested for different experimental conditions.
(A) Black: r = JMCT/Jglyco = 0.69/0.31 = 2.2 at basal state, as evaluated in vivo by Hyder et al. [28], with physiological values for intracellular lactate (Li) and pyruvate (P) concentrations (0.36 and 0.018 mM, respectively). Le = 1.1 mM. Dark gray: r = JMCT/Jglyco = 0.76/0.24 = 3.2, as observed in vitro by Bouzier-Sore et al. [15], with the experimentally used Le = 1.1 mM. Light gray: Le was increased to 5.5 mM, as described in the experiment by Bouzier-Sore et al. [16], resulting in a higher, but still plausible, value of 0.039 mM for intracellular pyruvate; r = 4.1. White: Same conditions as in light gray, but the glycolytic rate was lowered by 60%, resulting in a lower intracellular pyruvate concentration of 0.036 mM and a JMCT/Jglyco ratio equal to 0.92/0.08 = 11.5, which matches experimental results by Bouzier-Sore et al. [16]. (B) Effect of lactate transport enhancement in the case of a basal JMCT/Jglyco ratio (r) equal to 0.69/0.31 = 2.2, as evaluated in vivo by Hyder et al. [28], cf. black bar in (A). Basal state: Le = 1.1 mM (black). Stimulations: +30% vmax,PDH, +30% kshuttle, +48.5% vmax,glyco (very dark gray, ctrl-bar); +0% Le, +80% vmax,MCT, +70% vmax,PDH, +70% kshuttle (dark gray); +80% Le, +0% vmax,MCT, +70% vmax,PDH, +70% kshuttle (light gray); +80% Le, +80% vmax,MCT, +70% vmax,PDH, +70% kshuttle (white).