Perturbation of sphingolipid metabolism induces endoplasmic reticulum stress-mediated mitochondrial apoptosis in budding yeast
Perturbation of sphingolipid metabolism induces endoplasmic reticulum stress-mediated mitochondrial apoptosis in budding yeast
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DOI：
10.1111/mmi.12056
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发表时间：
2012-12-01
影响因子：
3.6
通讯作者：
Funato, Kouichi
中科院分区：
文献类型：
--
作者：
Kajiwara, Kentaro;Muneoka, Tetsuya;Funato, Kouichi
鞘脂是一类从酵母到哺乳动物保守的膜脂质，其决定细胞的死亡或存活。鞘脂代谢紊乱导致细胞凋亡。最近的研究表明，鞘脂水平降低会引发细胞死亡，但对其机制知之甚少。在芽殖酵母酿酒酵母中，我们发现复合鞘脂水平的降低导致活力的丧失，这很可能是由于诱导了线粒体和内质网形态学和内质网应激的变化，以及依赖于细胞凋亡的细胞死亡途径。细胞溶质游离钙升高是丧失生存力所必需的。这些结果表明，复杂的鞘脂是必不可少的维持内质网的稳态，并表明在复杂的鞘脂水平的扰动激活内质网应激介导的和钙依赖性途径传播凋亡信号的线粒体。
Sphingolipids are a class of membrane lipids conserved from yeast to mammals which determine whether a cell dies or survives. Perturbations in sphingolipid metabolism cause apoptotic cell death. Recent studies indicate that reduced sphingolipid levels trigger the cell death, but little is known about the mechanisms. In the budding yeast Saccharomyces cerevisiae, we show that reduction in complex sphingolipid levels causes loss of viability, most likely due to the induction of mitochondria-dependent apoptotic cell death pathway, accompanied by changes in mitochondrial and endoplasmic reticulum morphology and endoplasmic reticulum stress. Elevated cytosolic free calcium is required for the loss of viability. These results indicate that complex sphingolipids are essential for maintaining endoplasmic reticulum homeostasis and suggest that perturbation in complex sphingolipid levels activates an endoplasmic reticulum stress-mediated and calcium-dependent pathway to propagate apoptotic signals to the mitochondria.