Chemical inhibition of phosphatidylcholine biogenesis reveals its role in mitochondrial division
Hiroya Shiino,
Shinya Tashiro,
Michiko Hashimoto,
Yuki Sakata,
Takamitsu Hosoya,
Toshiya Endo,
Hirotatsu Kojima,
Yasushi Tamura
Affiliations
Hiroya Shiino
Graduate School of Global Symbiotic Sciences, Yamagata University, 1-4-12 Kojirakawa-machi, Yamagata 990-8560, Japan
Shinya Tashiro
Faculty of Science, Yamagata University, 1-4-12 Kojirakawa-machi, Yamagata, Yamagata 990-8560, Japan
Michiko Hashimoto
Faculty of Science, Yamagata University, 1-4-12 Kojirakawa-machi, Yamagata, Yamagata 990-8560, Japan
Yuki Sakata
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
Takamitsu Hosoya
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
Toshiya Endo
Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-motoyama, Kyoto 603-8555, Japan; Institute for Protein Dynamics, Kyoto Sangyo University, Kamigamo-motoyama, Kyoto 603-8555, Japan
Hirotatsu Kojima
Drug Discovery Initiative, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Summary: 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.
