Electronic journal of pathology and histopathology
Paginering:
Jaargang 6 (2002) nr. 1 pagina's 06
Jaar:
2002-03-25
Inhoud:
Despite many years of intensive studies, the role of intracellular calcium homeostasis in the regulation of cell death is still unclear and controversial. Partly, this is due to the lack of an understanding of cellular Ca2+ signaling processes in an integrated manner. While earlier studies on Ca2+ signaling have emphasized the interaction between the plasma membrane and the endoplasmic reticulum (ER) compartments, more recent work from several laboratories have clearly indicated the active participation of mitochondria in this intracellular Ca2+ network. It has now becoming recognized that mitochondria provide an important missing link in the mechanism whereby Ca2+ regulates apoptosis and necrosis. The purpose of this review is to summarize the role of mitochondria in calcium homeostasis and in the control of cell death. Apoptotic and nonapoptotic cell death is attracting enormous attention in virtually every aspect of modern pathology. While alterations in intracellular calcium homeostasis are commonly observed during apoptosis, the mechanism whereby calcium might regulate the apoptosis is still poorly understood. Previous studies from many laboratories have stressed the elevated cytoplasmic Ca2+ concentration (calcium overload) as a cause of cell injury. Excessive Ca2+ influx has been recognized as a key component of ischaemic brain damage for many years. Based on these findings, drugs such as the voltage-dependent calcium channel antagonists (nimodipine and flunarizine) have been tested in human clinical trials. However, the results from completed trials have been disappointing [25]. The lack of efficacy with these drugs in reducing neuronal cell injury has raised questions on the notion that Ca2+ overload is a pathogenic principle during ischaemic injury [25]. The status of Ca2+ homeostasis in cells undergoing apoptosis has not been clearly delineated. In some cases, elevated cytoplasmic Ca2+ (Cac) has been observed, and this condition has been suggested as a likely candidate to activate certain parts of the apoptosis cascade, such as the endonuclease responsible for internucleosomal DNA cleavage [reviewed in 28]. However, apoptosis of cultured neurons is attenuated by increasing Cac via the activation of voltage-gated Ca2+ channels [15, 22]. It appears that either too much or too little Ca2+ can pose problems for cell survival. The purpose of this review is to provide some recent advances on the role of Ca2+ homeostasis in the regulation of apoptosis and necrosis. Related issues are addressed in previous reviews [9, 28, 12].
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