Mitochondria and the control of intracellular calcium.

Abstract

Summary1.Because the calcium (Ca) ion is intimately associated with so many biochemical and physiological phenomena, it is fundamental to understand how intracellular Ca is maintained and controlled. This review draws attention to the vital role played by mitochondria in controlling intracellular Ca and describes how transport of the ion into and out of mitochondria may itself be controlled.2.The heterogeneous distribution of Ca is a property of most, if not all cells. This arises because the ion binds strongly to a variety of biological compounds, especially those containing oxyanions, which themselves have a heterogeneous distribution in cells, but mostly because of the existence in the cell of specific Ca‐ion transport systems.3.Although the concentration of total Ca in the cell may be quite high, a very large proportion of it is bound and non‐diffusible; a small fraction is diffusible but unionized. The proportion of Ca that is ionized is probably much less than I% of the total4.The mechanisms by which Ca is transported into and out of the mitochondrial matrix are discussed. Inward movement of the ion occurs in response to the membrane potential (negative inside) generated by respiration. The process is carrier‐mediated and exhibits characteristics such as substrate specificity, high affinity for Ca, satur‐ability, cooperativity, stimulation by permeant anions and is specifically inhibited by low concentrations of Ruthenium Red and lanthanum. The properties of the Ca carrier are geared therefore to facilitate rapid inward movement of Ca into the mitochondria. Such a carrier system is found in mitochondria isolated from a wide variety of tissues and species.5.Ionized Ca appears not to be distributed across the inner mitochondrial membrane according to the Nernst equation, so the possibility exists that the ion is transported as Ca/H+ antiport or as Ca/anion symport. Alternatively, an efflux system coupled to inward movement of a cation may serve to prevent the [Ca ion]in/[Ca ion]out from attaining equilibrium. These components together contribute to a Ca‐translocation cycle that permits Considerable flexibility in the overall control of Ca flux.6.Evidence for Ca cycling in mitochondria is presented and the influence of physiological agents such as Mg, phosphoenolpyruvate, inorganic phosphate and adenine nucleotides, on the influx and efflux components are discussed in some detail. Moreover, various hormones administered in vivo are able to induce changes in mitochondrial Ca cycling. One important feature that emerges from this collection of data is that the ability of mitochondria to retain Ca is associated with their ability to retain also their adenine‐nucleotide complement.7.Various lines of research provide convincing evidence in support of the view that mitochondria play a major role in controlling cell Ca in vivo. Especially significant are the observations that the ‘activity’ of mitochondrial Ca transport can change during development in both insect and mammalian tissue, can depend on the hormonal status of the tissue and undergoes a permanent change in certain tumour cells.8.Finally, consideration is given as to how the mitochondrial Ca transport system is able to modify Ca‐sensitive enzyme activities by regulating the Ca concentration in specific environments. Some biological activities that might be susceptible to such control are discussed.