209 Molecular and Cellular Biochemistry 256/257: 209–218, 2004. © 2004 Kluwer Academic Publishers. Printed in the Netherlands. Interplay between mitochondria and cellular calcium signalling Jake Jacobson and Michael R. Duchen Department of Physiology, University College London, London, UK Abstract Mitochondria are increasingly ascribed central roles in vital cell signalling cascades. These organelles are now recognised as initiators and transducers of a range of cell signals, including those central to activation and amplification of apoptotic cell death. Moreover, as the main source of cellular ATP, mitochondria must be responsive to fluctuating energy demands of the cell. As local and global fluctuations in calcium concentration are ubiquitous in eukaryotic cells and are the common factor in a dizzying array of intra- and inter-cellular signalling cascades, the relationships between mitochondrial function and calcium transients is currently a subject of intense scrutiny. It is clear that mitochondria not only act as local calcium buffers, thus shap- ing spatiotemporal aspects of cytosolic calcium signals, but that they also respond to calcium uptake by upregulating the tri- carboxylic acid cycle, thus reacting metabolically to local signalling. In this chapter we review current knowledge of mechanisms of mitochondrial calcium uptake and release and discuss the consequences of mitochondrial calcium handling for cell func- tion, particularly in conjunction with mitochondrial oxidative stress. (Mol Cell Biochem 256/257: 209–218, 2004) Key words: mitochondria, calcium, permeability transition pore, oxidative stress Introduction: A historical perspective Cellular calcium signalling seems to underpin an almost in- decent array of processes that involve the transition of cell activity from quiescent to active – be it contraction of mus- cle – smooth, cardiac, skeletal, secretion – of neurotransmitters, of hormones, of immunoactive compounds and cytokines, control of the cell cycle, of motility and so on and on. It has become standard practice in recent discussions on mitochon- drial involvement in cellular calcium handling to talk of a ‘renaissance’ in understanding of the roles of this remarkable organelle in relation to cellular calcium signalling. While it is true that work in the 1980s cast some doubt on the ability of mitochondria to take up calcium (Ca 2+ ) during physiologi- cal cytosolic [Ca 2+ ] c transients, evidence that mitochondria are well-equipped to participate intimately in Ca 2+ signalling has been available for decades. That mitochondria do indeed play a fundamental role in cellular signalling is now beyond ques- tion. Peter Mitchell’s chemiosmotic hypothesis of 1961 [1] provided a mechanism whereby the mitochondrial membrane potential (Δ Ψm ) could drive the passive electrophoretic uptake of cations into mitochondria. The fact that isolated mitochondria may accumulate Ca 2+ ions was established in the 1960s [2–5] followed by work in the 1970s that identified pathways for mitochondrial Ca 2+ ex- trusion [6, 7], beginning a debate on the stoichiometry of mi- tochondrial Ca 2+ uptake, buffering and release. Crucial for the development of understanding of the place of these pathways in cellular bioenergetics was the discovery by Denton et al. in the 1970s that the three rate limiting enzymes of the citric acid (or tricarboxylic acid, TCA) cycle (pyruvate dehydro- genase, 2-oxoglutarate dehydrogenase and NAD + -isocitrate dehydrogenase) are all activated by Ca 2+ [8–10], suggesting that the rate of ATP synthesis may be influenced by Ca 2+ uptake. Studies in brain [11], brain slices [12], synaptosomes [13], hepatocytes [14] and cardiomyocytes [15] all showed calcium dependent changes in mitochondrial function in re- sponse to physiological stimulation. In a series of experiments in the early 1990s, several groups showed that a physiologi- cal increase in [Ca 2+ ] c caused an increase in the mitochondrial Address for offprints: J. Jacobson, Department of Physiology, University College London, Gower Street, London, WC1E 6BT, UK (E-mail: j.jacobson@ucl.ac.uk)