Value of Control Theory in the Study of Cellular Metabolism — Biomedical Implications

Abstract

We use some examples to show that Metabolic Control Theory (MTC) not only allows the determination of the controlling steps of a metabolic network with the so-called control coefficients, but also leads to better understanding of the functioning of metabolic networks. The examples are taken partly from our own work on mitochondrial myopathies, partly from the literature: — the threshold effect observed in mitochondria diseases; — the problem of the diagnosis of complex I, II or III defects by measuring the NADH-cytochrome-c-reductase or the succinate-cytochrome-c-reductase activities with illustration by some cases. The possibility of a sum of control coefficients greater than one is also considered.

Energy Thresholds in Brain Mitochondria

“…In contrast to the different complex I thresholds present in synaptic and nonsynaptic mitochondria, complex III and IV thresholds in synaptic mitochondria are similar to those found in nonsynaptic mitochondria (26). These threshold effects are not restricted to brain mitochondria and have been have observed in rat muscle mitochondria for complex IV (40) and III (41), where the activity must be reduced by approximately 70 and 60%, respectively, before major changes in oxidative phosphorylation occur. The results shown in this study imply that the threshold effects for complexes III and IV will allow rat brain mitochondria to maintain near-optimal levels of oxidative phosphorylation even if their complex activities are reduced by up to 70%.…”

“…If the expression of this heteroplasmy of mtDNA is at the level of a given respiratory complex enzyme, then these may reinforce threshold effects observed in mitochondrial metabolism (40,41). Whether or not respiratory chain complex activities would be reduced sufficiently to seriously compromise oxidative phosphorylation would depend on the type of mitochondria effected.…”

Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia

“…It is possible to explain these findings within the framework of the metabolic control theory [58]. According to this theory, which investigates the effects of infinitesimally small parameter perturbations on the variables of metabolic systems, a crucial stage in the expression of a threshold for a clinical disease is, at molecular level, the impact that a localized defect in a given step has on the global flux of a metabolic network [58]. In this theory an important parameter is the control coefficient which quantitatively expresses the fractional change in pathway flux of a metabolic network, under steady-state conditions, induced by a fractional change in the individual step under consideration [57].…”

“…It is possible to explain these findings within the framework of the metabolic control theory [58]. According to this theory, which investigates the effects of infinitesimally small parameter perturbations on the variables of metabolic systems, a crucial stage in the expression of a threshold for a clinical disease is, at molecular level, the impact that a localized defect in a given step has on the global flux of a metabolic network [58].…”

Simple Models of Threshold Curves in the Expression of Inborn Errors of Metabolism: Application to some Experimental Observations

“…Oxidative phosphorylation deficiencies have also been experimentally mimicked, using specific inhibitors, and threshold curves have clearly been obtained [Letellier et al, 1993;Letellier et al, 1994;Malgat et al, 1995;Korzeniewski et al, 1996;Mazat et al, 1996;Letellier et al, 1997;Davey et al, 1997Davey et al, , 1998Davey and Clark, 1996;Villani and Attardi, 1997;Villani et al, 1998]. …”