Mechanism of apoptosis induced by zinc deficiency in peripheral blood T lymphocytes

Alterations in intracellular Zn2+ concentrations are believed to play a crucial role in modulating apoptosis. The observation that Zn2+ deficiency can induce cell death both in vivo and in vitro has been attributed to the fact that exchange of Zn2+ for Ca2+ and Mg2+ within the nuclei may directly activate endogenous endonucleases therefore inducing DNA fragmentation independent of cytoplasmic factors. Here we show that the membrane-permeable zinc chelator, N,N',N'-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) induces translocation of cytochrome c from the mitochondrial intramembranous space into the cytosol in human peripheral blood T lymphocytes (PBL) with subsequent activation of caspases-3, -8, and -9. Pretreatment of T lymphocytes with caspase inhibitors Z-VAD.fmk or DEVD.fmk prevented DNA fragmentation in response to TPEN indicating that apoptosis triggered by zinc deficiency is entirely dependent on activation of caspase family members. The release of cytochrome c and activation of downstream caspases precedes changes in the mitochondrial transmembrane potential (Delta Psim). Therefore, cytoplasmic and mitochondrial events are critical to this process.