Caspase-dependent and -independent lipotoxic cell-death pathways in fission yeast.
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.
Low
Choon Pei
CP
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore.
Shui
Guanghou
G
Liew
Li Phing
LP
Buttner
Sabrina
S
Madeo
Frank
F
Dawes
Ian W
IW
Wenk
Markus R
MR
Yang
Hongyuan
H
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000235:genetics; D002518:Ceramides / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D003470:Culture Media / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003603:Cytotoxins / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics; D004075:Diglycerides / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D050356:Lipid Metabolism / Q000235:genetics; D008055:Lipids / Q000494:pharmacology / Q000633:toxicity*; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D008954:Models, Biological; D030781:Organisms, Genetically Modified; D012568:Schizosaccharomyces / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D002518:Ceramides; D003470:Culture Media; D017077:Culture Media, Conditioned; D003603:Cytotoxins; D004075:Diglycerides; D008055:Lipids; D051048:Diacylglycerol O-Acyltransferase; D020169:Caspases