Quantitative Modeling of Pyruvate Dehydrogenase and its Impact in Substrate Selection, Mitochondrial Respiration and Redox

Abstract

The pyruvate dehydrogenase (PDH) complex plays a key role in substrate selection, primarily glucose and fatty acids (FAs). In mammals, substrate selection underlies metabolic remodeling and flexibility, and takes place in all organs although at different degrees depending on nutritional, health or disease conditions. Using a computational model encompassing carbohydrate and lipid catabolism (β-oxidation), we analyzed the role of PDH in substrate selection by mitochondria, accounting for regulation via multiple effectors (Acetyl CoA [AcCoA], CoA, NADH, NAD, ATP, ADP, Ca2+, pyruvate) which target specific kinases and phosphatases rendering phosphorylated (inactive) or dephosphorylated (active) the enzymatic complex. Mitochondrial selection between glucose and FAs was analyzed at different levels of both substrates through its impact on respiration, ROS emission, effector levels, and PDH and β-oxidation fluxes. In an integrated computational model of central catabolism, when cells are degrading glucose and FAs, AcCoA/CoA and NADH/NAD ratios modulation of PDH activity becomes crucial in substrate selection, in agreement with experimental data. Relative contributions to the AcCoA mitochondrial pool from glucose and FA catabolism were estimated at different ratios between pyruvate (Pyr) and palmitoyl CoA (PCoA). When Pyr increased at constant PCoA, the flux through PDH increased 3.6-fold whereas that of lipid transport decreased 15%. In contrast, increasing PCoA at constant Pyr produced ∼40% increase in lipid consumption as compared to ∼11% decrease through PDH. Respiration and H2O2 emission both increased as a function of PCoA/Pyr ratio, suggesting that ROS generation is matched by ROS scavenging. Results show that under conditions of different nutrient availability, the higher sensitivity of PDH toward glucose-derived substrates is in agreement with the crucial role played by this enzymatic complex in preserving glucose stores.