Ferroptosis occurs through an osmotic mechanism and propagates independently of cell rupture

Michelle Riegman, Liran Sagie, Chen Galed, Tom Levin, Noah Steinberg, Scott J. Dixon, Ulrich Wiesner, Michelle S. Bradbury, Philipp Niethammer, Assaf Zaritsky, Michael Overholtzer

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

Ferroptosis is a regulated form of necrotic cell death that is caused by the accumulation of oxidized phospholipids, leading to membrane damage and cell lysis1,2. Although other types of necrotic death such as pyroptosis and necroptosis are mediated by active mechanisms of execution3–6, ferroptosis is thought to result from the accumulation of unrepaired cell damage1. Previous studies have suggested that ferroptosis has the ability to spread through cell populations in a wave-like manner, resulting in a distinct spatiotemporal pattern of cell death7,8. Here we investigate the mechanism of ferroptosis execution and discover that ferroptotic cell rupture is mediated by plasma membrane pores, similarly to cell lysis in pyroptosis and necroptosis3,4. We further find that intercellular propagation of death occurs following treatment with some ferroptosis-inducing agents, including erastin2,9 and C′ dot nanoparticles8, but not upon direct inhibition of the ferroptosis-inhibiting enzyme glutathione peroxidase 4 (GPX4)10. Propagation of a ferroptosis-inducing signal occurs upstream of cell rupture and involves the spreading of a cell swelling effect through cell populations in a lipid peroxide- and iron-dependent manner.

Original languageEnglish
Pages (from-to)1042-1048
Number of pages7
JournalNature Cell Biology
Volume22
Issue number9
DOIs
StatePublished - 1 Sep 2020

ASJC Scopus subject areas

  • Cell Biology

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