Lipid peroxidation and the subsequent cell death transmitting from ferroptotic cells to neighboring cells

• Type of Material: Article
• Authors: Hironari Nishizawa, Tohoku University; Mitsuyo Matsumoto, Tohoku University; Guan Chen, Tohoku University; Yusho Ishii, Emory University; Keisuke Tada, Tohoku University; Masafumi Onodera, Natl Res Inst Child Hlth & Dev; Hiroki Kato, Tohoku University; Akihiko Muto, Tohoku University; Kozo Tanaka, Tohoku University; Kazuhiko Igarashi, Tohoku University
• Language: English
• Date: 2021-03-29
• Publisher: Springer Nature
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41419-021-03613-y
• Title of Journal or Parent Work: Cell Death & Disease
• Volume: 12
• Issue: 4
• Start Page: 332
• End Page: 332
• Grant/Funding Information: This work was supported in part by Grants-in-Aid from the Japan Society for the Promotion of Science 20K16296 and 19K23738 (to H. N.); Takeda Science Foundation (to H. N.), and Agency for Medical Research and Development Grant JP16gm050001 (to K. I.).; 19K07680 and 16K07108 (to M. M.) and 15H02506, 24390066, 21249014, and 18H04021 (to K. I.); Grant-in-Aid for Joint Research by Young Researchers (to H. N.), Gonryo Medical Foundation (to H. N.)
• Keywords: Ferroptotic cells; Life Sciences & Biomedicine; Cell death; Science & Technology; Lipid peroxidation; Cell Biology
• Research Categories: Biology, Molecular; Biology, Cell; Health Sciences, Oncology; Chemistry, Biochemistry

Abstract

Ferroptosis regulated cell death due to the iron-dependent accumulation of lipid peroxide. Ferroptosis is known to constitute the pathology of ischemic diseases, neurodegenerative diseases, and steatohepatitis and also works as a suppressing mechanism against cancer. However, how ferroptotic cells affect surrounding cells remains elusive. We herein report the transfer phenomenon of lipid peroxidation and cell death from ferroptotic cells to nearby cells that are not exposed to ferroptotic inducers (FINs). While primary mouse embryonic fibroblasts (MEFs) and NIH3T3 cells contained senescence-associated β-galactosidase (SA-β-gal)-positive cells, they were decreased upon induction of ferroptosis with FINs. The SA-β-gal decrease was inhibited by ferroptotic inhibitors and knockdown of Atg7, pointing to the involvement of lipid peroxidation and activated autophagosome formation during ferroptosis. A transfer of cell culture medium of cells treated with FINs, type 1 or 2, caused the reduction in SA-β-gal-positive cells in recipient cells that had not been exposed to FINs. Real-time imaging of Kusabira Orange-marked reporter MEFs cocultured with ferroptotic cells showed the generation of lipid peroxide and deaths of the reporter cells. These results indicate that lipid peroxidation and its aftereffects propagate from ferroptotic cells to surrounding cells, even when the surrounding cells are not exposed to FINs. Ferroptotic cells are not merely dying cells but also work as signal transmitters inducing a chain of further ferroptosis.