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

Hironari Nishizawa,Keisuke Tada,Kazuhiko Igarashi,Akihiko Muto,Yusho Ishii,Hiroki Kato,Kozo Tanaka,Guan Chen,Mitsuyo Matsumoto,Masafumi Onodera

doi:10.1038/s41419-021-03613-y

Abstract

Ferroptosis is a 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.

Highlights

The notion that dead cells are targeted for removal and important signal transmitters, sending signaling molecules to the surrounding cells and tissues, has recently been attracting attention[1,2,3,4]
We predicted that the SA-β-gal-positive cells might be increased during ferroptosis because lipid peroxidation and oxidative stress forcefully accumulate in ferroptotic cells[11,12,13]
The decrease in SA-β-gal-positive cells was still kept in NIH3T3 cells even 3 days after erastin was removed (Supplementary Fig. S3A–C), it was canceled or rather increased when erastin was removed and the mouse embryonic fibroblasts (MEFs) were recultured for 2 days (Fig. 1H–J and Supplementary Fig. S3D)

Summary

Introduction

The notion that dead cells are targeted for removal and important signal transmitters, sending signaling molecules to the surrounding cells and tissues, has recently been attracting attention[1,2,3,4]. Apoptotic cells secrete various substances that modulate proliferation[5,6], regeneration[7,8], and inflammation/ immunity[9,10] These observations suggest that signal transduction from cells undergoing regulated cell death processes plays important roles in the maintenance of Ferroptosis is iron-dependent-regulated necrosis-like cell death[11]. The Fenton reaction catalyzed by intracellular labile iron causes lipid peroxidation and hydroxyl-radical generation, leading to cell death[11,12,13]. This lipid peroxidation is considered the essential cause of ferroptosis. While repeated ischemic attacks are considered the cause of this extension of the affected area, it is possible that pathological lesions slowly spread

Methods

Results

Conclusion