The Effect of Ruthenium Red and Other Agents on Mitochondrial Calcium Metabolism

Abstract

The physiological consequences of pharmacological interventions that change mitochondrial Ca²⁺ will depend on the role of Ca²⁺ in the control of mitochondrial metabolism and on the adverse effects of increased Ca²⁺ load on mitochondrial function. Until quite recently, it was generally believed that the function of mitochondria in cellular Ca²⁺ metabolism was to provide a sink for Ca²⁺. This view arose principally from the relatively low affinity of the Ca²⁺ uniporter (mediating Ca²⁺ influx) for cytosolic Ca²⁺ together with the massive capacity for Ca²⁺ accumulation displayed by isolated mitochondria when presented with supraphysiological levels of Ca²⁺. Although mitochondria may act as an intracellular sink under pathological conditions, this capacity is most probably quite incidental to the natural role of the mitochondrial Ca²⁺ transport systems in controlling intramitochondrial free Ca²⁺ at low levels according to the regulatory requirements of oxidative metabolism. The capacity for Ca²⁺ accumulation is also constrained by the tolerance of mitochondrial function to increased Ca²⁺ load. It is important to stress that there are therefore two aspects to the behaviour of mitochondria with respect to Ca²⁺. These two aspects are indicated in Fig. 1.