Delineation of the molecular mechanism for disulfide stress-induced aluminium toxicity

Following our previous finding that the sulfhydryl-oxidising chemical diamide induced a marked elevation of cellular Al 3+ (Wu et al . , Int J Mol Sci, 12:8119–8132, 2011 ), a further investigation into the underlying molecular mechanism was carried out, using the eukaryotic model organism Saccharom...

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Bibliographic Details
Published in:Biometals 2012-06, Vol.25 (3), p.553-561
Main Authors: Wu, Ming J., Murphy, Patricia A., O’Doherty, Patrick J., Mieruszynski, Stephen, Jones, Mark, Kersaitis, Cindy, Rogers, Peter J., Bailey, Trevor D., Higgins, Vincent J.
Format: Article
Language:eng ; dut
Subjects:
Aluminium sulfate
Aluminum
Aluminum - pharmacology
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cellular
Deletion
Diamide - pharmacology
Disulfides - pharmacology
Dithiothreitol - pharmacology
Genes
Life Sciences
Medicine/Public Health
Microbiology
Molecular biology
Pharmacology/Toxicology
Plant Physiology
Saccharomyces cerevisiae - drug effects
Saccharomyces cerevisiae - metabolism
Screening
Stress analysis
Toxicity
Transporter
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Summary:Following our previous finding that the sulfhydryl-oxidising chemical diamide induced a marked elevation of cellular Al 3+ (Wu et al . , Int J Mol Sci, 12:8119–8132, 2011 ), a further investigation into the underlying molecular mechanism was carried out, using the eukaryotic model organism Saccharomyces cerevisiae . The effects of non-toxic dose of diamide (0.8 mM) and a mild dose of aluminium sulphate (Al 3+ ) (0.4 mM) were determined prior to the screening of gene deletion mutants. A total of 81 deletion mutants were selected for this study according to the available screening data against Al 3+ only (Kakimoto et al., BioMetals, 18: 467–474, 2005 ) and diamide only (Thorpe et al., Proc Natl Acad Sci USA, 101: 6564–6569, 2004 ). On the basis of our screening data and the cluster analysis, a cluster containing the gene deletions ( rpe1∆ , sec72∆ , pdr5∆ and ric1∆ ) was found to be specifically sensitive to the mixture of diamide and Al 3+ . However gnp1∆ , mch5∆ and ccc1∆ mutants were resistant. Dithiothreitol (DTT) and ascorbate markedly reversed the diamide-induced Al 3+ toxicity. Inductively-coupled plasma optical emission spectrometry demonstrated that DTT reduced the intracellular Al 3+ content in diamide/Al 3+ -treated yeast cells six-fold compared to the non-DTT controls. These data together revealed that the pleiotropic drug resistance transporter (Pdr5p) and vacuolar/vesicular transport-related proteins (Ric1p and Sec72p) are the targets of diamide. A dysfunctional membrane-bound Pdr5p terminates the detoxification pathway for Al 3+ at the final step, leading to intracellular Al 3+ accumulation and hence toxicity. As Al 3+ toxicity has been a problem in agriculture and human health, this study has provided a significant step forward in understanding Al 3+ toxicity.
ISSN:0966-0844
1572-8773
DOI:10.1007/s10534-012-9534-x