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

doi:10.1016/j.isci.2024.109189

Chemical inhibition of phosphatidylcholine biogenesis reveals its role in mitochondrial division

iScience. 2024 Feb 10;27(3):109189. doi: 10.1016/j.isci.2024.109189. eCollection 2024 Mar 15.

Authors

Hiroya Shiino¹, Shinya Tashiro², Michiko Hashimoto², Yuki Sakata³, Takamitsu Hosoya³, Toshiya Endo^{4

5}, Hirotatsu Kojima⁶, Yasushi Tamura²

Affiliations

¹ Graduate School of Global Symbiotic Sciences, Yamagata University, 1-4-12 Kojirakawa-machi, Yamagata 990-8560, Japan.
² Faculty of Science, Yamagata University, 1-4-12 Kojirakawa-machi, Yamagata, Yamagata 990-8560, Japan.
³ 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.
⁴ Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-motoyama, Kyoto 603-8555, Japan.
⁵ Institute for Protein Dynamics, Kyoto Sangyo University, Kamigamo-motoyama, Kyoto 603-8555, Japan.
⁶ Drug Discovery Initiative, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Abstract

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.

Keywords: Biochemistry; Biological sciences; Cell biology.