FAF1 blocks ferroptosis by inhibiting peroxidation of polyunsaturated fatty acids

Author:

Cui Shaojie1ORCID,Simmons Glenn1ORCID,Vale Goncalo12ORCID,Deng Yaqin1,Kim Jungyeon1,Kim Hyeonwoo1,Zhang Ruihui3ORCID,McDonald Jeffrey G.12,Ye Jin1ORCID

Affiliation:

1. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390

2. Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390

3. Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390

Abstract

Significance The current study reveals the functions of FAF1 in protecting cells from ferroptosis, a novel cell death pathway triggered by PUFA peroxidation. In the absence of FAF1, cultured cells and mice are extremely sensitive to ferroptosis when exposed to physiological levels of PUFAs. Mechanistically, FAF1 sequesters PUFAs into the hydrophobic core of a global structure that limits their access to positively charged Fe 2+ , which catalyzes the peroxidation reaction. These observations suggest that FAF1-mediated protection of PUFA peroxidation plays a critical role in preventing initiation of ferroptosis.

Funder

HHS | NIH | National Institute of General Medical Sciences

HHS | NIH | National Heart, Lung, and Blood Institute

Welch Foundation

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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