Regulation of caspase activation and apoptosis by cellular zinc fluxes and zinc deprivation: A review

Abstract

Summary Non-toxic agents that target intracellular signalling pathways in apoptosis may have potential therapeutic use in many diseases. One such agent is the transition metal Zn, a dietary cytoprotectant and anti-oxidant, which stimulates cell proliferation and suppresses apoptosis. Zn is maintained in discrete subcellular pools that are critical for the functional and structural integrity of cells. The present review initially describes the current state of knowledge on the cellular biology of Zn, especially the critical free or loosely bound (labile) pools of Zn, which are thought to regulate apoptosis. We then review the evidence relating Zn to apoptosis, including studies from our laboratory showing potent synergy between intracellular Zn deficiency and the short chain fatty acid butyrate in induction of caspase activation and the downstream events of apoptosis. Our studies have also reported the suppressive effects of micromolar concentrations of Zn on caspase-3 activation in cell-free models. Other key issues that will be discussed include the identification of the putative molecular targets of Zn and the evidence that systemic changes in labile Zn levels are sufficient to alter susceptibility to apoptosis and lead to physiopathological changes in the human body. Finally, we propose that labile Zn may serve as a coordinate regulator of mitosis and apoptosis to regulate tissue growth.

Oxidant-induced cell death in retinal pigment epithelium cells mediated through the release of apoptosis-inducing factor

“…Other investigators have demonstrated the disappearance of total cellular caspase-3 (Cai et al, 1999), an observation that is an imprecise measure of caspase activation. Under the influence of complete zinc depletion (Wood and Osborne, 2001), direct evidence of caspase-3 fragmentation has been shown in the RPE cells, but this is in stringent conditions that may have little relevance to the normal state of these cells (Chai et al, 1999;Hyun et al, 2001). A2E activation by blue light activates fluorescenic caspase-3 chromophorbes (Sparrow and Cai, 2001;Sparrow et al, 2002;Suter et al, 2000) but direct detection of caspase-3 fragments has not been presented.…”

Mammalian Zinc Transporters

“…Such a response to high zinc has led to the hypothesis that ZnT2 participates in a mechanism to regulate the involvement of zinc in apoptosis (8).…”

Testicular apoptosis after dietary zinc deficiency: Ultrastructural and TUNEL studies

“…The ability of Zn 2+ to prevent DNA fragmentation has been attributed to its inhibitory effect on Ca 2+ and Mg 2+ -dependent endonucleases Zhivotovsky et al 1994], although there are numerous targets of zinc in the apoptotic cascade such as caspase-3, caspase-6, bcl-2, p53, etc. [Takahashi et al 1996;Stennicke and Salvesen 1997;Wolf et al 1997;Fukamachi et al 1998;Chai et al 1999;Jankowski-Hennig et al 2000;Fanzo et al 2001;Ho and Ames 2002;Ho et al 2003], imbalance of either would lead to the initiation of apoptosis. Abnormally accelerated apoptosis of germ cells may lead to an imbalance of cell proliferation and death resulting in spermatogenic impairment [Hassan et al 2009].…”