Ferroptosis induces membrane blebbing in placental trophoblasts

Author:

Kajiwara Kazuhiro12ORCID,Beharier Ofer1ORCID,Chng Choon-Peng3ORCID,Goff Julie P.1,Ouyang Yingshi1ORCID,St Croix Claudette M.4ORCID,Huang Changjin35,Kagan Valerian E.6ORCID,Hsia K. Jimmy35,Sadovsky Yoel17ORCID

Affiliation:

1. Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA

2. Department of Obstetrics and Gynecology, Jikei University School of Medicine, Tokyo, Japan105-8461

3. School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore 639798, Republic of Singapore

4. Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA

5. School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637459, Republic of Singapore

6. Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA

7. Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA

Abstract

ABSTRACT Ferroptosis is a regulated, non-apoptotic form of cell death, characterized by hydroxy-peroxidation of discrete phospholipid hydroperoxides, particularly hydroperoxyl (Hp) forms of arachidonoyl- and adrenoyl-phosphatidylethanolamine, with a downstream cascade of oxidative damage to membrane lipids, proteins and DNA, culminating in cell death. We recently showed that human trophoblasts are particularly sensitive to ferroptosis caused by depletion or inhibition of glutathione peroxidase 4 (GPX4) or the lipase PLA2G6. Here, we show that trophoblastic ferroptosis is accompanied by a dramatic change in the trophoblast plasma membrane, with macro-blebbing and vesiculation. Immunofluorescence revealed that ferroptotic cell-derived blebs stained positive for F-actin, but negative for cytoplasmic organelle markers. Transfer of conditioned medium that contained detached macrovesicles or co-culture of wild-type target cells with blebbing cells did not stimulate ferroptosis in target cells. Molecular modeling showed that the presence of Hp-phosphatidylethanolamine in the cell membrane promoted its cell ability to be stretched. Together, our data establish that membrane macro-blebbing is characteristic of trophoblast ferroptosis and can serve as a useful marker of this process. Whether or not these blebs are physiologically functional remains to be established.

Funder

National Institutes of Health

25 Club of Magee-Womens Hospital

Magee-Womens Research Institute

Jikei University

Nanyang Technological University

Ministry of Education - Singapore

Publisher

The Company of Biologists

Subject

Cell Biology

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