Abstract
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 (Zn2+) is tightly controlled, as sustained increases in free Zn2+ 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 Zn2+ with mitochondrial dysfunction and the initiation of apoptosis. This apoptotic induction can be mimicked through addition of exogenous ZnCl2 and mitigated by zinc-chelation strategies, indicating Zn2+-dependent mechanisms in this process. However, the molecular mechanisms of Zn2+-mediated mitochondrial dysfunction are unknown. Here we report that free Zn2+ 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 Zn2+-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.
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Acknowledgments
This research was supported by a Ruth L. Kirschstein National Research Service Award Individual Fellowship, F32HL090198 (to D. A. Wiseman); National Institute of Health Grants HL-60190, HL-67841, HL-72123, HL084739, R21HD057406, and HL-70061, a Transatlantic Network Development Grant from Fondation LeDucq (all to S. M. Black), and an AHA Southeast affiliates Beginning Grant In Aid Award (09BGIA2310050, to S. Sharma).
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Wiseman, D.A., Sharma, S. & Black, S.M. Elevated zinc induces endothelial apoptosis via disruption of glutathione metabolism: role of the ADP translocator. Biometals 23, 19–30 (2010). https://doi.org/10.1007/s10534-009-9263-y
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DOI: https://doi.org/10.1007/s10534-009-9263-y