Acetic acid induces Sch9p-dependent translocation of Isc1p from the endoplasmic reticulum into mitochondria

Biochim Biophys Acta Mol Cell Biol Lipids. 2018 Jun;1863(6):576-583. doi: 10.1016/j.bbalip.2018.02.008. Epub 2018 Feb 27.

Abstract

Changes in sphingolipid metabolism have been linked to modulation of cell fate in both yeast and mammalian cells. We previously assessed the role of sphingolipids in cell death regulation using a well characterized yeast model of acetic acid-induced regulated cell death, finding that Isc1p, inositol phosphosphingolipid phospholipase C, plays a pro-death role in this process. Indeed, isc1∆ mutants exhibited a higher resistance to acetic acid associated with reduced mitochondrial alterations. Here, we show that Isc1p is regulated by Sch9p under acetic acid stress, since both single and double mutants lacking Isc1p or/and Sch9p have the same resistant phenotype, and SCH9 deletion leads to a higher retention of Isc1p in the endoplasmic reticulum upon acetic acid exposure. We also found that the higher resistance of all mutants correlates with higher levels of endogenous mitochondrial phosphorylated long chain bases (LCBPs), suggesting that changing the sphingolipid balance in favour of LCBPs in mitochondria results in increased survival to acetic acid. In conclusion, our results suggest that Sch9p pathways modulate acetic acid-induced cell death, through the regulation of Isc1p cellular distribution, thus affecting the sphingolipid balance that regulates cell fate.

Keywords: Acetic acid; Cell death; Cell signaling; Sphingolipids; Yeast.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetic Acid / pharmacology*
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Transport / drug effects
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Type C Phospholipases / genetics
  • Type C Phospholipases / metabolism*

Substances

  • Saccharomyces cerevisiae Proteins
  • Protein Serine-Threonine Kinases
  • SCH9 protein, S cerevisiae
  • ISC1 protein, S cerevisiae
  • Type C Phospholipases
  • Acetic Acid