Influence of substrate activation (hydrolysis of ATP by first steps of glycolysis and beta-oxidation) on the effect of enzyme deficiencies, inhibitors, substrate shortage and energy demand on oxidative phosphorylation.
In intact tissues respiratory substrates (glucose, fatty acids) must be activated with the use of ATP before they may be oxidised and used for energy (ATP) production. This activation by product constitutes an example of a typical positive feedback. In the present paper, the influence of substrate activation on the effect of inborn enzyme deficiencies, inhibitors, lowered oxygen tension, respiratory fuel shortage and increased energy demand on respiration and ATP synthesis is studied with the aid of the dynamic computer model of oxidative phosphorylation in isolated mitochondria developed previously. Computer simulations demonstrate that, in the case where oxidative phosphorylation in the whole organism is partially inhibited, the necessity of substrate activation can have significant impact on the relationship between the activity of (particular steps of) oxidative phosphorylation (or the value of energy demand) and the respiration rate. Depending on the sensitivity of ATP usage to ATP concentration, substrate activation may either slightly enhance the effect of the decrease in the oxidative phosphorylation activity (increase in energy demand) or may lead to a non-stability and sudden collapse of the respiration rate and phosphorylation potential below (above) a certain threshold value of oxidative phosphorylation activity (energy demand). This theoretical finding suggests a possible causal relationship between the affinity of ATP usage to [ATP] and the tissue specificity of mitochondrial diseases.
Korzeniewski
Bernard
B
Institute of Molecular Biology and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland. benio@mol.uj.edu.pl
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D003198:Computer Simulation; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D004798:Enzymes / Q000172:deficiency; D006019:Glycolysis; D006868:Hydrolysis; D066298:In Vitro Techniques; D007700:Kinetics; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000378:metabolism
D004791:Enzyme Inhibitors; D004798:Enzymes; D000255:Adenosine Triphosphate; D010100:Oxygen