title: Effect of enzyme deficiencies on oxidative phosphorylation: from isolated mitochondria to intact tissues. Theoretical studies.
abstract: The present article briefly summarizes the theoretical studies made by the authors and co-workers on the effect of inborn enzyme deficiencies on oxidative phosphorylation in intact tissues and on the genesis of mitochondrial diseases. The dynamic computer model of oxidative phosphorylation developed previously allowed to extrapolate experimental data (especially: threshold curves describing the dependence of oxygen consumption and ATP turnover on activities/concentrations of particular oxidative phosphorylation enzymes) obtained for isolated muscle mitochondria in state 3 at saturating oxygen concentrations to more physiological conditions prevailing in intact tissues. In particular, theoretical studies demonstrated that the threshold value of the relative activity/concentration of a given mitochondrial complex, below which a significant decrease in the respiration rate takes place, increases with an increase in energy demand. This fact was proposed as a possible explanation of the tissue specificity of mitochondrial diseases. Additionally, a decreased oxygen concentration was shown to increase the threshold value (and flux control coefficient) for cytochrome oxidase. We subsequently developed a model called 'binary mitochondria heteroplasmy', in which there are only two subpopulations of mitochondria: one 'wild-type' and one containing only defected molecules of a given enzyme. In this model we show that a defect has a pronounced effect on oxidative phosphorylation, significantly increasing the threshold value. It was also proposed that a parallel activation in the ATP supply-demand system during an increased energy demand significantly lessens the effect of enzyme deficiencies on oxidative phosphorylation (decreases the threshold value). Finally, the necessity of substrate activation may lead to an instability in the system and to appearance of a second threshold, below which respiration suddenly drops to zero, which is equivalent to the energetic death of a cell.
authors.affiliation: Institute of Molecular Biology and Biotechnology, Jagiellonian University, Kraków, Poland. benio@mol.uj.edu.pl
authors.forename: Bernard
authors.initials: B
authors.lastname: Korzeniewski
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D003198:Computer Simulation; D004272:DNA, Mitochondrial / Q000235:genetics; D004798:Enzymes / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D008931:Mitochondria, Muscle / Q000378:metabolism; D008954:Models, Biological; D010085:Oxidative Phosphorylation
chemical_list: D004272:DNA, Mitochondrial; D004798:Enzymes; D000255:Adenosine Triphosphate