A historical review of cellular calcium handling, with emphasis on mitochondria

Calcium ions are of central importance in cellular physiology, as they carry the signal activating cells to perform their programmed function. Ca2+ is particularly suitable for this role because of its chemical properties and because its free concentration gradient between the extra-cellular and the cytosolic concentrations is very high, about four orders of magnitude. The cytosolic concentration of Ca2+ is regulated by binding and chelation by various substances and by transport across plasma and intracellular membranes. Various channels, transport ATPases, uniporters, and antiporters in the plasma membrane, endoplasmic and sarcoplasmic reticulum, and mitochondria are responsible for the transport of Ca2+. The regulation of these transport systems is the subject of an increasing number of studies. In this short review, we focus on the mitochondrial transporters, i.e. the calcium uniporter used for Ca2+ uptake, and the antiporters used for the efflux, i.e. the Ca2+/Na+ antiporter in mitochondria and the plasma membrane of excitable cells, and the Ca2+/nH(+) antiporter in liver and some other mitochondrial types. Mitochondria are of special interest in that Ca2+ stimulates respiration and oxidative phosphorylation to meet the energy needs of activated cells. The studies on Ca2+ and mitochondria began in the fifties, but interest in mitochondrial Ca2+ handling faded in the late seventies since it had become apparent that mitochondria in resting cells contain very low Ca2+. Interest increased again in the nineties also because it was discovered that mitochondria and Ca2+ had a central role in apoptosis and necrosis. This is of special interest in calcium overload and oxidative stress conditions, when the opening of the mitochondrial permeability transition pore is stimulated.