Ferroptosis is an Autophagic Cell Death Process

Overview

Journal Cell Res

Specialty Cell Biology

Date 2016 Aug 13

PMID 27514700

Citations 773

Authors

Minghui Gao

Prashant Monian

Qiuhui Pan

Wei Zhang

Jenny Xiang

Xuejun Jiang

Affiliations

Soon will be listed here.

Abstract

Ferroptosis is an iron-dependent form of regulated necrosis. It is implicated in various human diseases, including ischemic organ damage and cancer. Here, we report the crucial role of autophagy, particularly autophagic degradation of cellular iron storage proteins (a process known as ferritinophagy), in ferroptosis. Using RNAi screening coupled with subsequent genetic analysis, we identified multiple autophagy-related genes as positive regulators of ferroptosis. Ferroptosis induction led to autophagy activation and consequent degradation of ferritin and ferritinophagy cargo receptor NCOA4. Consistently, inhibition of ferritinophagy by blockage of autophagy or knockdown of NCOA4 abrogated the accumulation of ferroptosis-associated cellular labile iron and reactive oxygen species, as well as eventual ferroptotic cell death. Therefore, ferroptosis is an autophagic cell death process, and NCOA4-mediated ferritinophagy supports ferroptosis by controlling cellular iron homeostasis.

Citing Articles

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References

Jiang L, Kon N, Li T, Wang S, Su T, Hibshoosh H . Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015; 520(7545):57-62. PMC: 4455927. DOI: 10.1038/nature14344. View

Tsujimoto Y, Shimizu S . Another way to die: autophagic programmed cell death. Cell Death Differ. 2005; 12 Suppl 2:1528-34. DOI: 10.1038/sj.cdd.4401777. View

Liu Y, Shoji-Kawata S, Sumpter Jr R, Wei Y, Ginet V, Zhang L . Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia. Proc Natl Acad Sci U S A. 2013; 110(51):20364-71. PMC: 3870705. DOI: 10.1073/pnas.1319661110. View

Dixon S, Lemberg K, Lamprecht M, Skouta R, Zaitsev E, Gleason C . Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012; 149(5):1060-72. PMC: 3367386. DOI: 10.1016/j.cell.2012.03.042. View

Mizushima N . Autophagy: process and function. Genes Dev. 2007; 21(22):2861-73. DOI: 10.1101/gad.1599207. View

Dolma S, Lessnick S, Hahn W, Stockwell B . Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell. 2003; 3(3):285-96. DOI: 10.1016/s1535-6108(03)00050-3. View

Mathew R, Karantza-Wadsworth V, White E . Role of autophagy in cancer. Nat Rev Cancer. 2007; 7(12):961-7. PMC: 2866167. DOI: 10.1038/nrc2254. View

Hou W, Xie Y, Song X, Sun X, Lotze M, Zeh 3rd H . Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. 2016; 12(8):1425-8. PMC: 4968231. DOI: 10.1080/15548627.2016.1187366. View

Mancias J, Wang X, Gygi S, Harper J, Kimmelman A . Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature. 2014; 509(7498):105-9. PMC: 4180099. DOI: 10.1038/nature13148. View

10.

Dowdle W, Nyfeler B, Nagel J, Elling R, Liu S, Triantafellow E . Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nat Cell Biol. 2014; 16(11):1069-79. DOI: 10.1038/ncb3053. View

11.

Green D, Kroemer G . The pathophysiology of mitochondrial cell death. Science. 2004; 305(5684):626-9. DOI: 10.1126/science.1099320. View

12.

Prus E, Fibach E . Flow cytometry measurement of the labile iron pool in human hematopoietic cells. Cytometry A. 2007; 73(1):22-7. DOI: 10.1002/cyto.a.20491. View

13.

Danial N, Korsmeyer S . Cell death: critical control points. Cell. 2004; 116(2):205-19. DOI: 10.1016/s0092-8674(04)00046-7. View

14.

Friedmann Angeli J, Schneider M, Proneth B, Tyurina Y, Tyurin V, Hammond V . Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014; 16(12):1180-91. PMC: 4894846. DOI: 10.1038/ncb3064. View

15.

Moriwaki K, Chan F . RIP3: a molecular switch for necrosis and inflammation. Genes Dev. 2013; 27(15):1640-9. PMC: 3744722. DOI: 10.1101/gad.223321.113. View

16.

Jiang X, Overholtzer M, Thompson C . Autophagy in cellular metabolism and cancer. J Clin Invest. 2015; 125(1):47-54. PMC: 4382242. DOI: 10.1172/JCI73942. View

17.

Dixon S, Patel D, Welsch M, Skouta R, Lee E, Hayano M . Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife. 2014; 3:e02523. PMC: 4054777. DOI: 10.7554/eLife.02523. View

18.

Vandenabeele P, Declercq W, Van Herreweghe F, Vanden Berghe T . The role of the kinases RIP1 and RIP3 in TNF-induced necrosis. Sci Signal. 2010; 3(115):re4. DOI: 10.1126/scisignal.3115re4. View

19.

Liu Y, Levine B . Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ. 2014; 22(3):367-76. PMC: 4326571. DOI: 10.1038/cdd.2014.143. View

20.

Mancias J, Vaites L, Nissim S, Biancur D, Kim A, Wang X . Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis. Elife. 2015; 4. PMC: 4592949. DOI: 10.7554/eLife.10308. View