Shiino Hiroya, Tashiro Shinya, Hashimoto Michiko, Sakata Yuki, Hosoya Takamitsu, Endo Toshiya, Kojima Hirotatsu, Tamura Yasushi
Graduate School of Global Symbiotic Sciences, Yamagata University, 1-4-12 Kojirakawa-machi, Yamagata 990-8560, Japan.
Faculty of Science, Yamagata University, 1-4-12 Kojirakawa-machi, Yamagata, Yamagata 990-8560, Japan.
iScience. 2024 Feb 10;27(3):109189. doi: 10.1016/j.isci.2024.109189. eCollection 2024 Mar 15.
Phospholipids are major components of biological membranes and play structural and regulatory roles in various biological processes. To determine the biological significance of phospholipids, the use of chemical inhibitors of phospholipid metabolism offers an effective approach; however, the availability of such compounds is limited. In this study, we performed a chemical-genetic screening using yeast and identified small molecules capable of inhibiting phosphatidylcholine (PC) biogenesis, which we designated PC inhibitors 1, 2, 3, and 4 (PCiB-1, 2, 3, and 4). Biochemical analyses indicated that PCiB-2, 3, and 4 inhibited the phosphatidylethanolamine (PE) methyltransferase activity of Cho2, whereas PCiB-1 may inhibit PE transport from mitochondria to the endoplasmic reticulum (ER). Interestingly, we found that PCiB treatment resulted in mitochondrial fragmentation, which was suppressed by expression of a dominant-negative mutant of the mitochondrial division factor Dnm1. These results provide evidence that normal PC biogenesis is important for the regulation of mitochondrial division.
磷脂是生物膜的主要成分，在各种生物过程中发挥结构和调节作用。为了确定磷脂的生物学意义，使用磷脂代谢的化学抑制剂提供了一种有效方法；然而，这类化合物的可用性有限。在本研究中，我们利用酵母进行了化学遗传学筛选，鉴定出能够抑制磷脂酰胆碱（PC）生物合成的小分子，我们将其命名为PC抑制剂1、2、3和4（PCiB-1、2、3和4）。生化分析表明，PCiB-2、3和4抑制了Cho2的磷脂酰乙醇胺（PE）甲基转移酶活性，而PCiB-1可能抑制PE从线粒体到内质网（ER）的转运。有趣的是，我们发现PCiB处理导致线粒体碎片化，而线粒体分裂因子Dnm1的显性负突变体的表达可抑制这种碎片化。这些结果证明正常的PC生物合成对于线粒体分裂的调节很重要。
