Elevated zinc induces endothelial apoptosis via disruption of glutathione metabolism: role of the ADP translocator
- 22 September 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in BioMetals
- Vol. 23 (1), 19-30
- https://doi.org/10.1007/s10534-009-9263-y
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.Keywords
This publication has 38 references indexed in Scilit:
- PAC-1 Activates Procaspase-3 in Vitro through Relief of Zinc-Mediated InhibitionJournal of Molecular Biology, 2009
- Nitric Oxide–Mediated Zinc Release Contributes to Hypoxic Regulation of Pulmonary Vascular ToneCirculation Research, 2008
- Hyperoxia Increases Phosphodiesterase 5 Expression and Activity in Ovine Fetal Pulmonary Artery Smooth Muscle CellsCirculation Research, 2008
- Nanoparticle interactions with zinc and iron: Implications for toxicology and inflammationToxicology and Applied Pharmacology, 2007
- Zinc modulates airway epithelium susceptibility to death receptor-mediated apoptosisAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2006
- Acute Glutathione Depletion Restricts Mitochondrial ATP Export in Cerebellar Granule NeuronsJournal of Biological Chemistry, 2005
- A possible cooperation of SOD1 and cytochrome c in mitochondria-dependent apoptosisFree Radical Biology & Medicine, 2005
- Ability of transgenic poplars with elevated glutathione content to tolerate zinc(2+) stressEnvironment International, 2004
- Superoxide Activates Mitochondrial Uncoupling Protein 2 from the Matrix SidePublished by Elsevier BV ,2002
- Intracellular free zinc and zinc buffering in human red blood cellsThe Journal of Membrane Biology, 1991