Valachovic Martin, Garaiova Martina, Holic Roman, Hapala Ivan
Institute of Animal Biochemistry and Genetics, Slovak Academy of Sciences, Moyzesova 61, 90028 Ivanka pri Dunaji, Slovak Republic.
Institute of Animal Biochemistry and Genetics, Slovak Academy of Sciences, Moyzesova 61, 90028 Ivanka pri Dunaji, Slovak Republic.
Biochem Biophys Res Commun. 2016 Jan 22;469(4):1123-8. doi: 10.1016/j.bbrc.2015.12.050. Epub 2015 Dec 15.
The toxic effect of overloaded lipids on cell physiology and viability was described in various organisms. In this study we focused on the potential lipotoxicity of squalene, a linear triterpene synthesized in eukaryotic cells as an intermediate in sterol biosynthesis. Squalene toxicity was studied in the yeast Saccharomyces cerevisiae, a model unicellular eukaryote established in lipotoxicity studies. Squalene levels in yeast are typically low but its accumulation can be induced under specific conditions, e.g. by inhibition of squalene monooxygenase with the antimycotic terbinafine. At higher levels squalene is stored in lipid droplets. We demonstrated that low doses of terbinafine caused severe impairment of growth and loss of viability of the yeast mutant dga1Δ lro1Δ are1Δ are2Δ unable to form lipid droplets and that these defects were linked to squalene accumulation. The hypersensitivity of the lipid droplet-less mutant to terbinafine was alleviated by decreasing squalene accumulation with low doses of squalene synthase inhibitor zaragozic acid. Our results proved that accumulated squalene is lipotoxic to yeast cells if it cannot be efficiently sequestered in lipid droplets. This supports the hypothesis about the role of squalene in the fungicidal activity of terbinafine. Squalene toxicity may represent also a limiting factor for production of this high-value lipid in yeast.
过量脂质对细胞生理和活力的毒性作用在多种生物体中都有描述。在本研究中,我们聚焦于角鲨烯的潜在脂毒性,角鲨烯是一种在真核细胞中合成的线性三萜,作为甾醇生物合成的中间体。我们在酿酒酵母中研究了角鲨烯的毒性,酿酒酵母是一种在脂毒性研究中建立的单细胞真核生物模型。酵母中的角鲨烯水平通常较低,但在特定条件下其积累可以被诱导,例如用抗真菌药特比萘芬抑制角鲨烯单加氧酶。在较高水平时,角鲨烯储存在脂滴中。我们证明,低剂量的特比萘芬会导致酵母突变体dga1Δ lro1Δ are1Δ are2Δ(无法形成脂滴)的生长严重受损和活力丧失,并且这些缺陷与角鲨烯积累有关。通过用低剂量的角鲨烯合酶抑制剂扎戈司亭降低角鲨烯积累,无脂滴突变体对特比萘芬的超敏性得到缓解。我们的结果证明,如果积累的角鲨烯不能有效地隔离在脂滴中,它对酵母细胞具有脂毒性。这支持了关于角鲨烯在特比萘芬杀菌活性中作用的假说。角鲨烯毒性也可能是酵母中这种高价值脂质生产的一个限制因素。