Elevated zinc induces endothelial apoptosis via disruption of glutathione metabolism: role of the ADP translocator.
Zinc is the second-most abundant transition metal within cells and an essential micronutrient. Although adequate zinc is essential for cellular function, intracellular free zinc (Zn(2+)) is tightly controlled, as sustained increases in free Zn(2+) levels can directly contribute to apoptotic endothelial cell death. Moreover, exposure of endothelial cells to acute nitrosative and/or oxidative stress induces a rapid rise of Zn(2+) with mitochondrial dysfunction and the initiation of apoptosis. This apoptotic induction can be mimicked through addition of exogenous ZnCl(2) and mitigated by zinc-chelation strategies, indicating Zn(2+)-dependent mechanisms in this process. However, the molecular mechanisms of Zn(2+)-mediated mitochondrial dysfunction are unknown. Here we report that free Zn(2+) disrupts cellular redox status through inhibition of glutathione reductase, and induces apoptosis by redox-mediated inhibition of the mitochondrial adenine nucleotide transporter (ANT). Inhibition of ANT causes increased mitochondrial oxidation, loss of ADP uptake, mitochondrial translocation of bax, and apoptosis. Interestingly, pre-incubation with glutathione ethyl ester protects endothelial cells from these observed effects. We conclude that key mechanisms of Zn(2+)-mediated apoptotic induction include disruption of cellular glutathione homeostasis leading to ANT inhibition and decreases in mitochondrial ATP synthesis. These pathways could represent novel therapeutic targets during acute oxidative or nitrosative stress in cells and tissues.
Wiseman
Dean A
DA
Vascular Biology Center, Medical College of Georgia, 1459 Laney Walker Blvd CB-3210, Augusta, GA 30912-2500, USA.
Sharma
Shruti
S
Black
Stephen M
SM
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D002712:Chlorides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism*; D012756:Sheep; D013329:Structure-Activity Relationship; D017967:Zinc Compounds / Q000494:pharmacology*
D002712:Chlorides; D017967:Zinc Compounds; D000244:Adenosine Diphosphate; C016837:zinc chloride; D000226:Mitochondrial ADP, ATP Translocases; D005978:Glutathione