The role of Ca²⁺ ions in the regulation of intramitochondrial metabolism and energy production in rat heart

Abstract

In the heart and other mammalian tissues, there are three exclusively intramitochondrial dehydrogenases that occupy key regulatory sites in oxidative metabolism which can be activated by increases in Ca²⁺ in the approximate range 0.05–5 μM; they are the pyruvate, NAD⁺-isocitrate and 2-oxoglutarate dehydrogenases. Activation of these enzymes can be demonstrated within intact mitochondria, incubated under expected physiological conditions, when the extramitochondrial concentration of Ca⁺ is raised within the expected physiological range. Recent studies with fura-2-loaded mitochondria have established that matrix Ca²⁺ is indeed in the 0.02–2 μM range as the enzymes are activated. There is now good evidence that in the rat heart, increases in cytoplasmic [Ca²⁺] caused by various inotropic agents result in increases in intramitochondrial Ca²⁺ and activation of these dehydrogenases. It is argued therefore that matrix Ca²⁺ may thus be a key regulator of oxidative phosphorylation under such circumstances. The major advantage of such a mechanism of dehydrogenase-based control of this process would be to the energy homeostasis of the cell by allowing stimulated ATP production without the need to decrease the ATP/ADP ratio. Therefore it is also proposed that the major function of the mitochondrial Ca²⁺-transport system is to regulate matrix Ca²⁺, and that the ability of mitochondria to buffer the extramitochondrial concentration of Ca²⁺ may thus only be reserved for pathophysiological conditions of abnormal sarcolemmal Ca²⁺ influx as perhaps may occur in ischaemia reperfusion.