Mechanism of apoptosis induced by zinc deficiency in peripheral blood T lymphocytes.
Alterations in intracellular Zn(2+) concentrations are believed to play a crucial role in modulating apoptosis. The observation that Zn(2+) deficiency can induce cell death both in vivo and in vitro has been attributed to the fact that exchange of Zn(2+) for Ca(2+) and Mg(2+) 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.
Kolenko
V M
VM
Department of Immunology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. kolenko@bbri.org
Uzzo
R G
RG
Dulin
N
N
Hauzman
E
E
Bukowski
R
R
Finke
J H
JH
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000494:pharmacology; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007425:Intracellular Membranes / Q000378:metabolism; D019169:Jurkat Cells; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D015032:Zinc / Q000172:deficiency* / Q000378:metabolism; D019014:fas Receptor / Q000096:biosynthesis
D000590:Amino Acid Chloromethyl Ketones; D002614:Chelating Agents; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D005029:Ethylenediamines; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D008274:Magnesium; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine; D002118:Calcium