Elevated zinc induces endothelial apoptosis via disruption of glutathione metabolism: Role of the ADP translocator

Dean A. Wiseman, Shruti Sharma, Stephen M. Black

Research output: Contribution to journalArticle

16 Scopus citations

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 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 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.

Original languageEnglish (US)
Pages (from-to)19-30
Number of pages12
JournalBioMetals
Volume23
Issue number1
DOIs
StatePublished - Feb 1 2010

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Keywords

  • Apoptosis
  • Mitochondrial dysfunction
  • Redox status

ASJC Scopus subject areas

  • Biomaterials
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Metals and Alloys

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