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Lipid Peroxidation-Dependent Cell Death Regulated by GPx4 and Ferroptosis

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Apoptotic and Non-apoptotic Cell Death

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 403))

Abstract

Glutathione peroxidase 4 (Phospholipid hydroperoxide glutathione peroxidase, PHGPx) can directly reduce phospholipid hydroperoxide. Depletion of GPx4 induces lipid peroxidation-dependent cell death in embryo, testis, brain, liver, heart, and photoreceptor cells of mice. Administration of vitamin E in tissue specific GPx4 KO mice restored tissue damage in testis, liver, and heart. These results indicate that suppression of phospholipid peroxidation is essential for cell survival in normal tissues in mice. Ferroptosis is an iron-dependent non-apoptotic cell death that can elicited by pharmacological inhibiting the cystine/glutamate antiporter, system Xc− (type I) or directly binding and loss of activity of GPx4 (Type II) in cancer cells with high level RAS-RAF-MEK pathway activity or p53 expression, but not in normal cells. Ferroptosis by Erastin (Type I) and RSL3 (RAS-selective lethal 3, Type II) treatment was suppressed by an iron chelator, vitamin E and Ferrostatin-1, antioxidant compound. GPx4 can regulate ferroptosis by suppression of phospholipid peroxidation in erastin and RSL3-induced ferroptosis. Recent works have identified several regulatory factors of erastin and RSL3-induced ferroptosis. In our established GPx4-deficient MEF cells, depletion of GPx4 induce iron and 15LOX-independent lipid peroxidation at 26 h and caspase-independent cell death at 72 h, whereas erastin and RSL3 treatment resulted in iron-dependent ferroptosis by 12 h. These results indicated the possibility that the mechanism of GPx4-depleted cell death might be different from that of ferroptosis induced by erastin and RSL3.

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Abbreviations

GPx4:

Glutathione peroxidase

mGPx4:

Mitochondrial GPx4

cGPx4:

Non-mitochondrial GPx4

nGPx4:

Nucleolar GPx4

tBid:

Truncated Bid

CL:

Cardiolipin

TG:

Transgenic

MEF:

Mouse embryonic fibroblast

RSL:

Ras-Selective Lethal

Tam:

Tamoxifen

GSH:

Glutathione

LOX:

Lipoxygenase

DFO:

Deferoxamine

Fer-1:

Ferrostatin-1

LOX:

Lipoxygenase

PC:

Phosphatidylcholine

PE:

Phosphatidylethanolamine

ACSL4:

Acyl-CoA synthetase long-chain family member 4

AA:

Arachidonic acid

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Acknowledgements

We thank H. Nakano and S. Nagata for helpful comments on the manuscript. We also thank members of Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kitasato University for helpful discussion. This work was supported in part by Grants-in-Aid from Scientific Research (C) (26460075) from JSPS KAKENHI and Scientific Research on Innovative Areas (15H01386 and 16H01367) from a MEXT (Ministry of Education, Culture, Sports, Science and Technology), Japan, and research grants from Iijima Tojyuro Memorial Food Science Foundation and Kitasato University Research Grant for Young Researchers.

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The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan

    Hirotaka Imai, Masaki Matsuoka, Takeshi Kumagai, Taro Sakamoto & Tomoko Koumura

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  1. Hirotaka Imai
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  2. Masaki Matsuoka
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  3. Takeshi Kumagai
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  4. Taro Sakamoto
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  5. Tomoko Koumura
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Correspondence to Hirotaka Imai .

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Editors and Affiliations

  1. Biochemistry & Immunology, WPI Immunology frontier research center, Osaka University, Osaka, Japan

    Shigekazu Nagata

  2. Department of Biochemistry, Toho University School of Medicine, Tokyo, Tokyo, Japan

    Hiroyasu Nakano

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Imai, H., Matsuoka, M., Kumagai, T., Sakamoto, T., Koumura, T. (2016). Lipid Peroxidation-Dependent Cell Death Regulated by GPx4 and Ferroptosis. In: Nagata, S., Nakano, H. (eds) Apoptotic and Non-apoptotic Cell Death. Current Topics in Microbiology and Immunology, vol 403. Springer, Cham. https://doi.org/10.1007/82_2016_508

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