Display Settings:

Format

Send to:

Choose Destination
We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Cell Metab. 2012 Jul 3;16(1):90-6. doi: 10.1016/j.cmet.2012.06.004.

Sphingolipid signaling mediates iron toxicity.

Author information

  • 1Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095-1569, USA.

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.

Copyright © 2012 Elsevier Inc. All rights reserved.

PMID:
22768841
[PubMed - indexed for MEDLINE]
PMCID:
PMC3653578
Free PMC Article

Images from this publication.See all images (4)Free text

Figure 1
Figure 2
Figure 3
Figure 4
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk