Sphingolipid signaling mediates iron toxicity

Yueh Jung Lee, Xinhe Huang, Janette Kropat, Anthony Henras, Sabeeha S. Merchant, Robert C. Dickson, Guillaume F. Chanfreau

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Iron constitutes a major source of toxicity due to its ability to generate reactive oxygen species that can damage cellular macromolecules. However, the precise mechanism by which exposure to high iron concentrations results in cellular toxicity remains unknown. Here we identify sphingolipid synthesis and signaling as a major mediator of iron toxicity in S. cerevisiae. Inhibition of sphingolipid synthesis by myriocin treatment or after overexpression of the negative regulator Orm2p confers resistance to high iron. High iron conditions upregulate sphingolipid synthesis, and increasing sphingolipid levels by inactivating Orm2p exacerbates sensitivity to iron. Toxicity is mediated by sphingolipid signaling, as inactivation of the sphingolipid-activated protein kinases Pkh1p and Ypk1p and of the transcription factor Smp1p also enhances resistance to high iron conditions. These results demonstrate an unexpected connection between sphingolipid flux and iron toxicity and show that activation of a signal transduction cascade contributes to iron-mediated cellular toxicity.

Original languageEnglish
Pages (from-to)90-96
Number of pages7
JournalCell Metabolism
Volume16
Issue number1
DOIs
StatePublished - Jul 3 2012

Bibliographical note

Funding Information:
We thank S. Covarrubias for help with the construction of the genomic library; I. Toesca for help with initials screens, R. Lester for advice on sphingolipid analyses; and C. Clarke, J. Valentine, and J. Torres for discussions. This work is supported by NIGMS grant GM61518 to G.F.C., grant AG024377 to R.C.D., and grant DOE-DE-FG02- 04ER15529 to S.S.M.

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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