Sphingolipid Signaling Mediates Iron Toxicity

SummaryIron 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (161 K)Download as PowerPoint slideHighlights► Inhibiting sphingolipid synthesis allows yeast to grow in higher iron conditions ► Yeasts exposed to high iron increase sphingolipid production ► High iron conditions activate sphingolipid signaling ► Inhibiting Pkh1p/Ypk1p/Smp1p signaling confers relative resistance to iron toxicity