BioMetals

, Volume 25, Issue 3, pp 553–561

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

  • Ming J. Wu
  • Patricia A. Murphy
  • Patrick J. O’Doherty
  • Stephen Mieruszynski
  • Mark Jones
  • Cindy Kersaitis
  • Peter J. Rogers
  • Trevor D. Bailey
  • Vincent J. Higgins
Article

DOI: 10.1007/s10534-012-9534-x

Cite this article as:
Wu, M.J., Murphy, P.A., O’Doherty, P.J. et al. Biometals (2012) 25: 553. doi:10.1007/s10534-012-9534-x
  • 232 Downloads

Abstract

Following our previous finding that the sulfhydryl-oxidising chemical diamide induced a marked elevation of cellular Al3+ (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 (Al3+) (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 Al3+ 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 Al3+. However gnp1∆, mch5∆ and ccc1∆ mutants were resistant. Dithiothreitol (DTT) and ascorbate markedly reversed the diamide-induced Al3+ toxicity. Inductively-coupled plasma optical emission spectrometry demonstrated that DTT reduced the intracellular Al3+ content in diamide/Al3+-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 Al3+ at the final step, leading to intracellular Al3+ accumulation and hence toxicity. As Al3+ toxicity has been a problem in agriculture and human health, this study has provided a significant step forward in understanding Al3+ toxicity.

Keywords

Disulfide stress Diamide Aluminium Toxicity Yeast 

Supplementary material

10534_2012_9534_MOESM1_ESM.xls (22 kb)
Supplementary material 1 (XLS 22 kb)

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Ming J. Wu
    • 1
  • Patricia A. Murphy
    • 1
  • Patrick J. O’Doherty
    • 1
  • Stephen Mieruszynski
    • 1
  • Mark Jones
    • 1
  • Cindy Kersaitis
    • 1
  • Peter J. Rogers
    • 2
    • 3
  • Trevor D. Bailey
    • 1
  • Vincent J. Higgins
    • 4
  1. 1.School of Science and HealthUniversity of Western SydneyPenrithAustralia
  2. 2.Carlton and United BreweriesFosters GroupMelbourneAustralia
  3. 3.School of ScienceGriffith UniversitySouth BrisbaneAustralia
  4. 4.Ramaciotti Centre for Gene Function Analysis, School of Biotechnology and Biomolecular SciencesUniversity of New South WalesSydneyAustralia

Personalised recommendations