The kinetic basis of threshold effects observed in mitochondrial diseases: a systemic approach.

Threshold effects in the expression of metabolic diseases have often been observed in mitochondrial pathologies, i.e. the clinical demonstration of the disease appears only when the activity of a step has been reduced to a rather low level. We show experimentally that an inhibition of cytochrome c oxidase activity by cyanide, simulating a defect in this step, leads to a decrease in mitochondrial respiration which then exhibits a threshold behaviour similar to that observed in mitochondrial diseases. We discuss this behaviour in terms of metabolic control theory and construct a mathematical model simulating this behaviour.