What is d effect of increased intracellular calcium in apoptosis?
Answers
A clear impetus in the study of Ca2+ homeostasis in apoptosis came from the observation that important regulatory of apoptosis, the proteins of the Bcl-2 family, are localized in organelles deeply involved in Ca2+ handling (the mitochondria and the ER). Indeed, Bcl-2 has been detected in association with the outer mitochondrial membrane, with the ER and with the nucleus and a cytoplasmic form of Bcl-2 is also known to exist (Pinton and Rizzuto, 2006). Although most investigators agree with the idea that only Bcl-2 bound to membranes is involved in inhibiting cell death, the mechanism, the importance and function of Bcl-2 in different cellular locations are still a matter of controversy.
The first association between Bcl-2 and Ca2+ homeostasis dates back to 1993, when Bcl-2 overexpression was shown to prevent the reduction in the Ca2+ concentration of the ER ([Ca2+]ER) that was observed upon the withdrawal of interleukin-3 in hematopoietic cell lines (Baffy et al., 1993). This effect was not secondary to the antiapoptotic effect of Bcl-2 (e.g., preventing the loss of energy and thus of ER Ca2+; during apoptosis), as Bcl-2 overexpression was also reported to decrease the size of the ER Ca2+ released (Lam et al., 1994). These observations were further expanded into a comprehensive picture where targeted probes allowed a detailed subcellular analysis of Ca2+ homeostasis and the complex signals controlling mitochondrial participation at least partially unveiled. In these experiments, an ER-targeted aequorin chimera (Pinton et al., 2007b) was transiently coexpressed with Bcl-2 in HeLa cells. No toxicity due to Bcl-2 transient overexpression was observed, in distinction to the experiments in which a Bcl-2-GFP chimera was used (Wang et al., 2001). Rather, as expected, the cells overexpressing Bcl-2 displayed an enhanced survival upon ceramide treatment (Pinton et al., 2001b), in agreement with previous reports (Zhang et al., 1996; Rippo et al., 2000) Most strikingly, compared with controls, Bcl-2 overexpressing cells showed a ~30% reduction in the Ca2+ levels within both the ER and the Golgi apparatus. As a consequence, the [Ca2+] increases elicited in these cells by stimuli coupled to IP3 generation were reduced both in the cytoplasm and in the mitochondria (Pinton et al., 2000).
drastically reduced upon ceramide treatment (Pinton et al., 2001b). Conversely, cell lines derived from calreticulin knockouts, that show a marked decrease in ER Ca2+ release upon cell stimulation, are more resistant to apoptosis (Nakamura et al., 2000).