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First published online 24 July 2008
doi: 10.1242/jcs.028977

Journal of Cell Science 121, 2671-2684 (2008)
Published by The Company of Biologists 2008
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Research Article

Caspase-dependent and -independent lipotoxic cell-death pathways in fission yeast

Choon Pei Low1, Guanghou Shui1, Li Phing Liew1, Sabrina Buttner2, Frank Madeo2, Ian W. Dawes3, Markus R. Wenk1 and Hongyuan Yang1,3,*

1 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore
2 Institute of Molecular Biosciences, University of Graz, Universitätsplatz 2, 8010 Graz, Austria
3 School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, 2052 New South Wales, Australia

* Author for correspondence (e-mail: h.rob.yang{at}unsw.edu.au)

Accepted 19 May 2008

Understanding the mechanisms underlying lipid-induced cell death has significant implications in both cell biology and human diseases. Previously, we showed that fission-yeast Schizosaccharomyces pombe cells deficient in triacylglycerol synthesis display apoptotic markers upon entry into stationary phase. Here, we characterize the sequential molecular events that take place at the onset of cell death in S. pombe, including a surge of diacylglycerol, post-mitotic arrest, alterations in mitochondrial activities and in intracellular redox balance, chromatin condensation, nuclear-envelope fragmentation, and eventually plasma-membrane permeabilization. Our results demonstrated active roles of mitochondria and reactive oxygen species in cell death, and identified novel cell-death regulators – including metacaspase Pca1, BH3-domain protein Rad9, and diacylglycerol-binding proteins Pck1 and Bzz1. Most importantly, we show that, under different conditions and stimuli, failure to maintain intracellular-lipid homeostasis can lead to cell death with different phenotypic manifestations, genetic criteria and cellular mechanisms, pointing to the existence of multiple lipotoxic pathways in this organism. Our study represents the first in-depth analysis of cell-death pathways in S. pombe.

Key words: Apoptosis, Fission yeast, Lipotoxicity, Metacaspase, Mitochondria, Programmed cell death


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