Low Choon Pei, Shui Guanghou, Liew Li Phing, Buttner Sabrina, Madeo Frank, Dawes Ian W, Wenk Markus R, Yang Hongyuan
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore.
J Cell Sci. 2008 Aug 15;121(Pt 16):2671-84. doi: 10.1242/jcs.028977. Epub 2008 Jul 24.
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.
了解脂质诱导的细胞死亡背后的机制在细胞生物学和人类疾病方面都具有重要意义。此前，我们发现缺乏三酰甘油合成能力的裂殖酵母粟酒裂殖酵母细胞在进入稳定期时会表现出凋亡标记物。在此，我们描述了粟酒裂殖酵母细胞死亡开始时发生的一系列分子事件，包括二酰甘油激增、有丝分裂后停滞、线粒体活性变化和细胞内氧化还原平衡改变、染色质凝聚、核膜破裂，最终质膜通透性增加。我们的结果证明了线粒体和活性氧在细胞死亡中的积极作用，并鉴定出了新的细胞死亡调节因子，包括metacaspase Pca1、BH3结构域蛋白Rad9以及二酰甘油结合蛋白Pck1和Bzz1。最重要的是，我们表明，在不同条件和刺激下，无法维持细胞内脂质稳态会导致具有不同表型表现、遗传标准和细胞机制的细胞死亡，这表明该生物体中存在多种脂毒性途径。我们的研究是对粟酒裂殖酵母细胞死亡途径的首次深入分析。
