The role of zinc in caspase activation and apoptotic cell death

In addition to its diverse role in many physiological systems, zinc (Zn) ha s now been shown to be an important regulator of apoptosis. The purpose of this review is to integrate previously published knowledge on Zn and apopto sis with current attempts to elucidate the mechanisms of action of this bio metal. This paper begins with an introduction to apoptosis and then briefly reviews the evidence relating Zn to apoptosis. The major focus of this rev iew is the mechanistic actions of Zn and its candidate intracellular target s. In particular, we examine the cytoprotective functions of Zn which suppr ess major pathways leading to apoptosis, as well as the more direct influen ce of Zn on the apoptotic regulators, especially the caspase family of enzy mes. These two mechanisms are closely related since a decline in intracellu lar Zn below a critical threshold level may not only trigger pathways leadi ng to caspase activation but may also facilitate the process by which the c aspases are activated. Studies by our laboratory in airway epithelial cells show that Zn is co-localized with the precursor form of caspase-3, mitocho ndria and microtubules, suggesting this Zn is critically placed to control apoptosis. Further understanding the different pools of Zn and how they int eract with apoptotic pathways should have importance in human disease.