Mitochondrial Ca2+ Signalling

Historically, the role played by mitochondria in cellular Ca2+ homeostasis has been the subject of considerable controversy (Fiskum & Lehninger, 1982; Akerman & Nicholls, 1983). The view that mitochondria, by virtue of possessing a huge capacity for Ca2+ uptake (Lehninger, 1967) act in the cell as mobilizable stores of the ion (Exton, 1980) capable of regulating cytosolic Ca2+ (Nicholls, 1978) has seen a considerable revision of the past 10–15 years (Denton & McCormack, 1980; Hansford, 1994; Crompton, 1985; McCormack et al., 1990; Denton & McCormack, 1986). This resulted firstly from the recognition that Ca2+ cycles constantly across the inner mitochondrial inner membrane (Nicholls & Crompton, 1980), so that the concentration of Ca2+ within the mitochondrial matrix ([Ca2+]m) is related to cytosolic Ca2+ by the kinetic properties of the transporters, rather than purely thermodynamic considerations. Thus, intramitochondrial Ca2+ concentrations in the low micromolar range have become generally accepted, rather than earlier assumptions of [Ca2+]m levels in the millimolar range or higher. Secondly, mitochondria from all vertebrate sources studied so far, as well as certain plants, have been shown to possess three important intramitochondrial oxidative enzymes whose activity is controlled in the micromolar range of Ca2+ ions (Denton et al., 1972; Denton et al., 1978; McCormack & Denton, 1979; Rutter, 1990). These findings led to the model first proposed by Denton and McCormack (Denton & McCormack, 1980) that increases in intramitochondrial Ca2+ concentration ([Ca2+]m), triggered after stimulus-induced increases in cytosolic free calcium concentration ([Ca2+]c), could activate oxidative metabolism, generating NADH or the respiratory chain, and enhanced ATP synthesis. This would then fuel the Ca2+-activated ATP-requiring events in the cytosol, such as muscle contraction, secretion or gene expression, without requiring a drop in intracellular ATP levels. Considerable evidence supporting this model has accrued since its proposal. For reviews see (McCormack et al., 1990; Denton & McCormack, 1990). However, support for the model has been considered to be at odds with the view that mitochondria could play any significant role in controlling cytosolic [Ca2+].