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Abstract: Local Ca2+ transfer between adjoining domains of the sarcoendoplasmic reticulum (ER/SR) and mitochondria allows ER/SR Ca2+ release to activate mitochondrial Ca2+ uptake and to evoke a matrix [Ca2+] ([Ca2+]m) rise. [Ca2+]m exerts control on several steps of energy metabolism to synchronize ATP generation with cell function. However, calcium signal propagation to the mitochondria may also ignite a cell death program through opening of the permeability transition pore (PTP). This occurs when the Ca2+ release from the ER/SR is enhanced or is coincident with sensitization of the PTP. Recent studies have shown that several pro-apoptotic factors, including members of the Bcl-2 family proteins and reactive oxygen species (ROS) regulate the Ca2+ sensitivity of both the Ca2+ release channels in the ER and the PTP in the mitochondria. To test the relevance of the mitochondrial Ca2+ accumulation in various apoptotic paradigms, methods are available for buffering of [Ca2+], for dissipation of the driving force of the mitochondrial Ca2+ uptake and for inhibition of the mitochondrial Ca2+ transport mechanisms. However, in intact cells, the efficacy and the specificity of these approaches have to be established. Here we discuss mechanisms that recruit the mitochondrial calcium signal to a pro-apoptotic cascade and the approaches available for assessment of the relevance of the mitochondrial Ca2+ handling in apoptosis. We also present a systematic evaluation of the effect of ruthenium red and Ru360, two inhibitors of mitochondrial Ca2+ uptake on cytosolic [Ca2+] and [Ca2+]m in intact cultured cells. [Copyright &y& Elsevier]

Intracellular Ca2+ is able to control numerous cellular responses through complex spatial and temporal organization. For the effective handling of intracellular Ca2+, endoplasmic reticulum (ER) Ca2+ mobilization and plasma membrane Ca2+ entry have to be complemented by strategic and dynamic positioning of an energy source that is usually provided by mitochondrial ATP production. Mitochondria also participate in the transport of Ca2+. Mitochondria are dynamically distributed in cells and utilize cytoskeletal tracks and motor proteins for their movements. Recent studies have reported that Ca2+ inhibits mitochondrial motility providing a mechanism to retain mitochondria at Ca2+ signalling sites. Here we discuss the control of the mitochondrial distribution by cell signalling mechanisms, the spatial relationship among individual mitochondria and ER domains, and the possible implications of mitochondrial movements in the Ca(2+)-dependent cell survival and cell death mechanisms.