Voltage-dependent anion channels (VDACs) are expressed in three isoforms, with common channeling properties and different roles in cell survival. We show that VDAC1 silencing potentiates apoptotic challenges, whereas VDAC2 has the opposite effect. Although all three VDAC isoforms are equivalent in allowing mitochondrial Ca 2 þ loading upon agonist stimulation, VDAC1 silencing selectively impairs the transfer of the low-amplitude apoptotic Ca 2 þ signals. Co-immunoprecipitation experiments show that VDAC1, but not VDAC2 and VDAC3, forms complexes with IP 3 receptors, an interaction that is further strengthened by apoptotic stimuli. These data highlight a non-redundant molecular route for transferring Ca 2 þ signals to mitochondria in apoptosis.
In the complex interplay that allows different signals to be decoded into activation of cell death, calcium (Ca2+) plays a significant role. In all eukaryotic cells, the cytosolic concentration of Ca2+ ions ([Ca2+]c) is tightly controlled by interactions among transporters, pumps, channels and binding proteins. Finely tuned changes in [Ca2+]c modulate a variety of intracellular functions ranging from muscular contraction to secretion, and disruption of Ca2+ handling leads to cell death. In this context, Ca2+ 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 Ca2+ 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.
Despite the growing interest in the Fhit tumor suppressor protein, frequently deleted in human cancers, the mechanism of its powerful proapoptotic activity has remained elusive. We here demonstrate that Fhit sensitizes the low-affinity Ca 2؉ transporters of mitochondria, enhancing Ca 2؉ uptake into the organelle both in intact and in permabilized cells, and potentiating the effect of apoptotic agents. This effect can be attributed to the fraction of Fhit sorted to mitochondria, as a fully mitochondrial Fhit (a chimeric protein including a mitochondrial targeting sequence) retains the Ca 2؉ signaling properties of Fhit and the proapoptotic activity of the native protein (whereas the effects on the cell cycle are lost). Thus, the partial sorting of Fhit to mitochondria allows to finely tune the sensitivity of the organelle to the highly pleiomorphic Ca 2؉ signals, synergizing with apoptotic challenges. This concept, and the identification of the molecular machinery, may provide ways to act on apoptotic cell death and its derangement in cancer.calcium signaling ͉ mitochondria ͉ oncosopressor ͉ oxidative stress T he fragile histidine triad (FHIT) gene, isolated by positional cloning, encompasses the most common human fragile site FRA3B at 3p14.2. This chromosomal region is involved in hemizygous and homozygous deletions, and indeed mutations of FHIT were demonstrated in a large variety of human tumors (1-4). FHIT encodes a 17-kDa protein (Fhit) that is abundantly expressed in normal human lung, stomach, kidney, and other epithelial tissues, whereas most tumors and tumor-derived cell lines do not express Fhit or show markedly reduced levels of the protein (5). Fhit knock-out mice are more susceptible to cancer development than their wild-type counterparts (6), and FHIT gene therapy can prevent and reverse tumors in carcinogen-exposed Fhit-deficient mice (7). However, the precise molecular mechanism involved in the antitumor function of FHIT remains largely unclear.Fhit is partly localized in mitochondria, and interaction with Hsp60/ Hsp10 could be important for correct refolding after import and Fhit stability (8). This compartmentalization of Fhit could reveal a transcription-independent regulation of cell fate. Indeed, mitochondria are at the crossroad of numerous apoptotic pathways that synergize in triggeringthemorphologicaltransitionsunderlyingthereleaseofproapoptotic factors into the cytoplasm (9-11). In most cases, Ca 2ϩ acts as a fundamental sensitizing factor, and anti-apoptotic proteins, such as Bcl-2, have been shown to reduce ER Ca 2ϩ levels, and agonistdependent release and mitochondrial loading (12)(13)(14).Different agents induce Ca 2ϩ release from the ER Ca 2ϩ store through the IP 3 R Ca 2ϩ release channel (15). Consequent mitochondrial Ca 2ϩ uptake, via a yet unidentified Ca 2ϩ channel of the inner mitochondrial membrane (the mitochondrial Ca 2ϩ uniporter, MCU), regulates different processes: Aerobic metabolism (16), release of caspase cofactors (17), and feedback control of neighboring ER or plasma ...
Mitochondrial Ca 2 þ uptake controls cellular functions as diverse as aerobic metabolism, cytosolic Ca 2 þ signalling and mitochondrial participation in apoptosis. Modulatory inputs converging on the organelle can regulate this process, determining the final outcome of Ca 2 þ -mediated cell stimulation. We investigated in HeLa cells and primary skeletal myotubes the effect on Ca 2 þ signalling of the transcriptional peroxisome-proliferator-activated-receptor-c-coactivator-1a (PGC-1a), which triggers organelle biogenesis and modifies the mitochondrial proteome. PGC-1a selectively reduced mitochondrial Ca 2 þ responses to cell stimulation by reducing the efficacy of mitochondrial Ca 2 þ uptake sites and increasing organelle volume. In turn, this affected ER Ca 2 þ release and cytosolic responses in HeLa cells. Most importantly, the modulation of mitochondrial Ca 2 þ uptake significantly reduced cellular sensitivity to the Ca 2 þ -mediated proapoptotic effect of C 2 ceramide. These results reveal a primary role of PGC-1a in shaping mitochondrial participation in calcium signalling, that underlies its protective role against stress and proapoptotic stimuli in pathophysiological conditions.
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