Kinetic Modeling of the Mitochondrial Energy Metabolism of Neuronal Cells: The Impact of Reduced 𝛼-Ketoglutarate Dehydrogenase Activities on ATP Production and Generation of Reactive Oxygen Species

Figure 1

Schematic of the mathematical model. Pyruvate (Pyr) is the only substrate of the TCA cycle. Pyruvate is decarboxylated by pyruvate dehydrogenase (PDH) to acetyl-CoA (ACoA), which is then condensed with oxaloacetate (OA) to citrate (Cit) via the citrate synthase (CS). Citrate is converted to isocitrate (IsoCit) by the aconitase (AC), which is further converted to α-ketoglutarate (aKG) via the isocitrate dehydrogenase (IDH) producing NADH from NAD in the process. The α-ketogluterate dehydrogenase complex (KGDHC) catalyses the reaction of α-ketogluterate with Coenzyme A to succinyl-CoA (SucCoA) under reduction of NAD to NADH. Succinyl-CoA is further metabolized by succinyl-CoA synthase (SCS) to succinate (Suc) by phosphorylating ADP to ATP (substrate-chain phosphorylation). Succinate is dehydrogenated to fumarate (Fum) by the succinate dehydrogenase (SDH, complex II) reducing ubiquinone to ubiquinol (see legend of Figure 2). Fumerase (FUM) converts fumerate to malate (Mal), which is oxidized by malate dehydrogenase (MDH) again producing one NADH and regenerating the initial oxalacetate so the cycle can start over again. In summary, PDH and the TCA cycle produce one ATP from ADP, one ubiquinol from ubiquinone, and four NADHs from NAD while oxidizing one pyruvate to three CO₂. Oxidation of NADH and/or succinate in the respiratory chain, is coupled to transmembrane proton pumping which generates a proton gradient and a mitochondrial membrane potential. The proton gradient is used to fuel pyruvate uptake from the cytosol into the matrix via pyruvate transporter, pumping of sodium, potassium from the matrix into the intermembrane space/cytosol, phosphate transport from the cytosol into the matrix space, and ATP generation by the F0F1-ATPase. The mitochondrial membrane potential drives the ATP/ADP exchange between the matrix and the intermembrane space/cytosol. The model also comprises the passive exchange of protons, sodium, potassium and chloride between the matrix and the intermembrane space/cytosol driven by electrodiffusion as well as the mitochondrial membrane potential. Cytosolic ATP is hydrolyzed to ADP and phosphate to meet the energy demand of the cell.