Kinetic Model of Mitochondrial Krebs Cycle: Unraveling the Mechanism of Salicylate Hepatotoxic Effects

Abstract

This paper studies the effect of salicylate on the energy metabolism of mitochondria using in silico simulations. A kinetic model of the mitochondrial Krebs cycle is constructed using information on the individual enzymes. Model parameters for the rate equations are estimated using in vitro experimental data from the literature. Enzyme concentrations are determined from data on respiration in mitochondrial suspensions containing glutamate and malate. It is shown that inhibition in succinate dehydrogenase and α-ketoglutarate dehydrogenase by salicylate contributes substantially to the cumulative inhibition of the Krebs cycle by salicylates. Uncoupling of oxidative phosphorylation has little effect and coenzyme A consumption in salicylates transformation processes has an insignificant effect on the rate of substrate oxidation in the Krebs cycle. It is found that the salicylate-inhibited Krebs cycle flux can be increased by flux redirection through addition of external glutamate and malate, and depletion in external α-ketoglutarate and glycine concentrations.

Metabolomic Study on Idiosyncratic Liver Injury Induced by Different Extracts of Polygonum multiflorum in Rats Integrated with Pattern Recognition and Enriched Pathways Analysis

“…They could be considered as potential markers for biological pathway analysis. Previous studies showed that one of the reasons for drug induced liver injury is the disturbance of the hepatocyte energy metabolism, particularly in the Krebs cycle (Mogilevskaya et al, 2006). In the experiment, TCA cycle may be most related to the hepatotoxicity of EA.…”

The biochemistry of ketogenesis and its role in weight management, neurological disease and oxidative stress

“…This arises from the ability of salicylates to inhibit the enzymes of the TCA cycle (specifically succinate dehydrogenase and α-ketoglutarate dehydrogenase). This leads to increased formation of lactate, which is then converted into ketone bodies [32].…”

Attractor Metabolic Networks

“…Most of these functional biochemical studies have been carried out by means of systems of differential equations e.g., the Krebs cycle [18], the amino acid biosynthetic pathways [19], the oxidative phosphorylation subsystem [20], the glycolytic subsystem [21], the transduction in G-protein enzyme cascade [22], the gene expression [23], the cell cycle [24]. Likewise, in order to understand the emerging dynamics in a multienzymatic set dissipatively structured we have also researched the yeast glycolytic subsystem by using a system of differential equations with delay [25].…”