Ca2+ signaling mechanisms of cell survival and cell death: An introduction (original) (raw)
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Ca2+ Signaling, Mitochondria and Cell Death
Current Molecular Medicine, 2008
In the complex interplay that allows different signals to be decoded into activation of cell death, calcium (Ca 2+ ) plays a significant role. In all eukaryotic cells, the cytosolic concentration of Ca 2+ ions ([Ca 2+ ]c) is tightly controlled by interactions among transporters, pumps, channels and binding proteins. Finely tuned changes in [Ca 2+ ]c modulate a variety of intracellular functions ranging from muscular contraction to secretion, and disruption of Ca 2+ handling leads to cell death. In this context, Ca 2+ signals have been shown to affect important checkpoints of the cell death process, such as mitochondria, thus tuning the sensitivity of cells to various challenges. In this contribution, we will review (i) the evidence supporting the involvement of Ca 2+ in the three major process of cell death: apoptosis, necrosis and autophagy (ii) the complex signaling interplay that allows cell death signals to be decoded into mitochondria as messages controlling cell fate and the direct investigation of Ca 2+ signaling, and its cellular targets in autophagy, represents a fascinating challenge for the years to come.
Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis
Oncogene, 2008
There is a growing consensus that the various forms of cell death (necrosis, apoptosis and autophagy) are not separated by strict boundaries, but rather share molecular effectors and signaling routes. Among the latter, a clear role is played by calcium (Ca 2+ ), the ubiquitous second messenger involved in the control of a broad variety of physiological events. Fine tuning of intracellular Ca 2+ homeostasis by anti-and proapoptotic proteins shapes the Ca 2+ signal to which mitochondria and other cellular effectors are exposed, and hence the efficiency of various cell death inducers. Here, we will review: (i) the evidence linking calcium homeostasis to the regulation of apoptotic, and more recently autophagic cell death, (ii) the discussion of mitochondria as a critical, although not unique checkpoint and (iii) the molecular and functional elucidation of ER/mitochondria contacts, corresponding to the mitochondria-associated membrane (MAM) subfraction and proposed to be a specialized signaling microdomain.
Cell Calcium, 2006
Local Ca 2+ transfer between adjoining domains of the sarcoendoplasmic reticulum (ER/SR) and mitochondria allows ER/SR Ca 2+ release to activate mitochondrial Ca 2+ uptake and to evoke a matrix [Ca 2+ ] ([Ca 2+ ] m ) rise. [Ca 2+ ] 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 Ca 2+ 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 Ca 2+ sensitivity of both the Ca 2+ release channels in the ER and the PTP in the mitochondria. To test the relevance of the mitochondrial Ca 2+ accumulation in various apoptotic paradigms, methods are available for buffering of [Ca 2+ ], for dissipation of the driving force of the mitochondrial Ca 2+ uptake and for inhibition of the mitochondrial Ca 2+ 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 Ca 2+ handling in apoptosis. We also present a systematic evaluation of the effect of ruthenium red and Ru360, two inhibitors of mitochondrial Ca 2+ uptake on cytosolic [Ca 2+ ] and [Ca 2+ ] m in intact cultured cells.
Mitochondrial Ca2+ and apoptosis
Cell Calcium, 2012
Mitochondria are key decoding stations of the apoptotic process. In support of this view, a large body of experimental evidence has unambiguously revealed that, in addition to the well-established function of producing most of the cellular ATP, mitochondria play a fundamental role in triggering apoptotic cell death.
Mitochondria, calcium and pro-apoptotic proteins as mediators in cell death signaling
Brazilian Journal of Medical and Biological Research, 2003
Cellular Ca 2+ signals are crucial in the control of most physiological processes, cell injury and programmed cell death through the regulation of a number of Ca 2+ -dependent enzymes such as phospholipases, proteases, and nucleases. Mitochondria along with the endoplasmic reticulum play pivotal roles in regulating intracellular Ca 2+ content. Mitochondria are endowed with multiple Ca 2+ transport mechanisms by which they take up and release Ca 2+ across their inner membrane. During cellular Ca 2+ overload, mitochondria take up cytosolic Ca 2+ , which in turn induces opening of permeability transition pores and disrupts the mitochondrial membrane potential (Dy m ). The collapse of Dy m along with the release of cytochrome c from mitochondria is followed by the activation of caspases, nuclear fragmentation and cell death. Members of the Bcl-2 family are a group of proteins that play important roles in apoptosis regulation. Members of this family appear to differentially regulate intracellular Ca 2+ level. Translocation of Bax, an apoptotic signaling protein, from the cytosol to the mitochondrial membrane is another step in this apoptosis signaling pathway.
Calcium and mitochondria in cell death
The calcium ion has long been known to play an important role in cell death regulation. Hence, necrotic cell death was early associated with intracellular Ca 2þ overload, leading to mitochondrial permeability transition and functional collapse. Subsequent characterization of the signaling pathways in apoptosis revealed that Ca 2þ /calpain was critically involved in the processing of the mitochondrially localized, Apoptosis Inducing Factor. More recently, the calcium ion has been demonstrated to play important regulatory roles also in other cell death modalities, notably autophagic cell death and anoikis. In this review, we summarize current knowledge about the mechanisms involved in Ca 2þ regulation of these various modes of cell death with a focus on the importance of the mitochondria.
Ca2+ signalling in mitochondria: mechanism and role in physiology and pathology
Cell Calcium, 2003
Over recent years, a renewed interest in mitochondria in the field of Ca 2+ signalling has highlighted their central role in regulating important physiological and pathological events in animal cells. Mitochondria take up calcium through an uptake pathway that, due to its low-Ca 2+ affinity, demands high local calcium concentrations to work. In different cell systems high-Ca 2+ concentration microdomains are generated, upon cell stimulation, in proximity of either plasma membrane or sarco/endoplasmic reticulum Ca 2+ channels. Mitochondrial Ca 2+ accumulation has a dual role, an universal one, which consists in satisfying energy demands by increasing the ATP production through the activation of mitochondrial enzymes, and a cell type specific one, which, through the modulation of the spatio-temporal dynamics of calcium signals, contributes to modulate specific cell functions. Recent work has revealed the central role of mitochondria dysfunction in determining both necrotic and apoptotic cell death. Evidence is also accumulating that suggests that alterations in mitochondrial function may act as predisposing factors in the pathogenesis of a number of neurodegenerative disorders. These include inherited disorders of the mitochondrial genome in which a defect in mitochondrial calcium accumulation has been shown to correlate with a defect in ATP production, thus suggesting a possible involvement of mitochondrial Ca 2+ dysfunction also for this group of diseases. This review analyses recent developments in the area of mitochondrial Ca 2+ signalling and attempts to summarise cell physiology and cell pathology aspects of the mitochondrial Ca 2+ transport machinery.
Calcium and apoptosis: facts and hypotheses
Oncogene, 2003
Although longstanding experimental evidence has associated alterations of calcium homeostasis to cell death, only in the past few years the role of calcium in the signaling of apoptosis has been extensively investigated. In this review, we will summarize the current knowledge, focusing on (i) the effect of the proteins of the Bcl-2 family on ER Ca 2 þ levels, (ii) the action of the proteolytic enzymes of apoptosis on the Ca 2 þ signaling machinery, (iii) the ensuing alterations on the signaling patterns of extracellular stimuli, and (iv) the intracellular targets of 'apoptotic' Ca 2 þ signals, with special emphasis on the mitochondria and cytosolic Ca 2 þ -dependent enzymes.