Abstract
Ferroptosis is a non-apoptotic form of cell death characterized by overwhelming iron-dependent lipid peroxidation, which contributes to a number of pathologies, most notably tissue ischemia/reperfusion injury, neurodegeneration and cancer. Cysteine availability, glutathione biosynthesis, polyunsaturated fatty acid metabolism and modulation of the phospholipidome are the key events of this necrotic cell death pathway. Non-enzymatic and enzymatic lipoxygenase (LOX)-mediated lipid peroxidation of lipid bilayers is efficiently counteracted by the glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis. Preliminary studies suggest that bursting ferroptotic cells release pro-inflammatory damage-associated molecular patterns (DAMPs) that trigger the innate immune system as exemplified by diseased kidney and brain tissues where ferroptosis contributes to organ demise in a predominant manner. The GSH/GPX4 node is known to control the activities of LOX and prostaglandin-endoperoxide synthase (PTGS) via the so-called peroxide tone. Since LOX and PTGS products do have pro- and anti-inflammatory effects, one may speculate that these enzymes contribute to the ferroptotic process on several levels in cell-autonomous and non-autonomous ways. Hence, this review provides the reader with an outline on what is currently known about the link between ferroptosis and necroinflammation and discusses critical events that may alert the innate immune system in early phases when cells become sensitized towards ferroptosis.
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References
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.
Conrad M, Angeli JP, Vandenabeele P, Stockwell BR. Regulated necrosis: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2016;15:348–66.
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273–85.
Green DR, Ferguson T, Zitvogel L, Kroemer G. Immunogenic and tolerogenic cell death. Nat Rev Immunol. 2009;9:353–63.
Linkermann A, Stockwell BR, Krautwald S, Anders HJ. Regulated cell death and inflammation: an auto-amplification loop causes organ failure. Nat Rev Immunol. 2014;14:759–67.
Bannai S, Kitamura E. Transport interaction of L-cystine and L-glutamate in human diploid fibroblasts in culture. J Biol Chem. 1980;255:2372–6.
Kobayashi S, Sato M, Kasakoshi T, Tsutsui T, Sugimoto M, Osaki M, et al. Cystathionine is a novel substrate of cystine/glutamate transporter: implications for immune function. J Biol Chem. 2015;290:8778–88.
Bannai S. Exchange of cystine and glutamate across plasma membrane of human fibroblasts. J Biol Chem. 1986;261:2256–63.
Gout PW, Buckley AR, Simms CR, Bruchovsky N. Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x(c)- cystine transporter: a new action for an old drug. Leukemia. 2001;15:1633–40.
Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife. 2014;3:e02523.
Mandal PK, Seiler A, Perisic T, Kolle P, Banjac Canak A, Forster H, et al. System x(c)- and thioredoxin reductase 1 cooperatively rescue glutathione deficiency. J Biol Chem. 2010;285:22244–53.
Griffith OW. Depletion of glutathione by inhibition of biosynthesis. Method Enzymol. 1981;77:59–63.
Hayano M, Yang WS, Corn CK, Pagano NC, Stockwell BR. Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ. 2016;23:270–8.
Gao M, Monian P, Quadri N, Ramasamy R, Jiang X. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell. 2015;59:298–308.
Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014;16:1180–91.
Yang WS, Sriramaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156:317–31.
Ursini F, Maiorino M, Valente M, Ferri L, Gregolin C. Purification from pig liver of a protein which protects liposomes and biomembranes from peroxidative degradation and exhibits glutathione peroxidase activity on phosphatidylcholine hydroperoxides. Biochim Biophys Acta. 1982;710:197–211.
Weiwer M, Bittker JA, Lewis TA, Shimada K, Yang WS, MacPherson L, et al. Development of small-molecule probes that selectively kill cells induced to express mutant RAS. Bioorg Med Chem Lett. 2012;22:1822–6.
Woo JH, Shimoni Y, Yang WS, Subramaniam P, Iyer A, Nicoletti P, et al. Elucidating compound mechanism of action by network perturbation analysis. Cell. 2015;162:441–51.
Seiler A, Schneider M, Forster H, Roth S, Wirth EK, Culmsee C, et al. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 2008;8:237–48.
Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. 2017;13:81–90.
Dixon SJ, Winter GE, Musavi LS, Lee ED, Snijder B, Rebsamen M, et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem Biol. 2015;10:1604–9.
Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13:91–8.
Shah R, Shchepinov MS, Pratt DA. Resolving the role of lipoxygenases in the initiation and execution of ferroptosis. ACS Cent Sci. 2018;4:387–96.
Friedmann Angeli JP, Conrad M. Lipoxygenases—killers against their will? ACS Cent Sci. 2018;4:312–4.
Zilka O, Shah R, Li B, Friedmann Angeli JP, Griesser M, Conrad M, et al. On the mechanism of cytoprotection by ferrostatin-1 and liproxstatin-1 and the role of lipid peroxidation in ferroptotic cell death. ACS Cent Sci. 2017;3:232–43.
Angeli JPF, Shah R, Pratt DA, Conrad M. Ferroptosis inhibition: mechanisms and opportunities. Trends Pharmacol Sci. 2017;38:489–98.
Shimada K, Skouta R, Kaplan A, Yang WS, Hayano M, Dixon SJ, et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol. 2016;12:497–503.
Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017;547:453–7.
Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 2007;447:864–8.
Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol. 2008;15:234–45.
Gao M, Monian P, Pan Q, Zhang W, Xiang J, Jiang X. Ferroptosis is an autophagic cell death process. Cell Res. 2016;26:1021–32.
Gaschler MM, Andia AA, Liu H, Csuka JM, Hurlocker B, Vaiana CA, et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol. 2018;14:507–15.
Yant LJ, Ran Q, Rao L, Van Remmen H, Shibatani T, Belter JG, et al. The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radic Biol Med. 2003;34:496–502.
Chen L, Hambright WS, Na R, Ran Q. Ablation of the ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis. J Biol Chem. 2015;290:28097–106.
Hambright WS, Fonseca RS, Chen L, Na R, Ran Q. Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol. 2017;12:8–17.
Wirth EK, Bharathi BS, Hatfield D, Conrad M, Brielmeier M, Schweizer U. Cerebellar hypoplasia in mice lacking selenoprotein biosynthesis in neurons. Biol Trace Elem Res. 2014;158:203–10.
Wirth EK, Conrad M, Winterer J, Wozny C, Carlson BA, Roth S, et al. Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration. FASEB J. 2010;24:844–52.
Schriever SC, Zimprich A, Pfuhlmann K, Baumann P, Giesert F, Klaus V, et al. Alterations in neuronal control of body weight and anxiety behavior by glutathione peroxidase 4 deficiency. Neuroscience. 2017;357:241–54.
Carlson BA, Tobe R, Yefremova E, Tsuji PA, Hoffmann VJ, Schweizer U, et al. Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration. Redox Biol. 2016;9:22–31.
Matsushita M, Freigang S, Schneider C, Conrad M, Bornkamm GW, Kopf M. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J Exp Med. 2015;212:555–68.
Ueta T, Inoue T, Furukawa T, Tamaki Y, Nakagawa Y, Imai H, et al. Glutathione peroxidase 4 is required for maturation of photoreceptor cells. J Biol Chem. 2012;287:7675–82.
Wortmann M, Schneider M, Pircher J, Hellfritsch J, Aichler M, Vegi N, et al. Combined deficiency in glutathione peroxidase 4 and vitamin e causes multiorgan thrombus formation and early death in mice. Circ Res. 2013;113:408–17.
Linkermann A, Skouta R, Himmerkus N, Mulay SR, Dewitz C, De Zen F, et al. Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci USA. 2014;111:16836–41.
Tuo QZ, Lei P, Jackman KA, Li XL, Xiong H, Liuyang ZY, et al. Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry. 2017;22:1520–30.
Li Q, Han X, Lan X, Gao Y, Wan J, Durham F, et al. Inhibition of neuronal ferroptosis protects hemorrhagic brain. JCI Insight. 2017;2:e90777.
Wang H, An P, Xie E, Wu Q, Fang X, Gao H, et al. Characterization of ferroptosis in murine models of hemochromatosis. Hepatology. 2017;66:449–65.
Gascon S, Murenu E, Masserdotti G, Ortega F, Russo GL, Petrik D, et al. Identification and successful negotiation of a metabolic checkpoint in direct neuronal reprogramming. Cell Stem Cell. 2016;18:396–409.
Skouta R, Dixon SJ, Wang J, Dunn DE, Orman M, Shimada K, et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc. 2014;136:4551–6.
Kim SE, Zhang L, Ma K, Riegman M, Chen F, Ingold I, et al. Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth. Nat Nanotechnol. 2016;11:977–85.
Cramer SL, Saha A, Liu J, Tadi S, Tiziani S, Yan W, et al. Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth. Nat Med. 2017;23:120–7.
Louandre C, Ezzoukhry Z, Godin C, Barbare JC, Maziere JC, Chauffert B, et al. Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib. Int J Cancer. 2013;133:1732–42.
Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520:57–62.
Wang SJ, Li D, Ou Y, Jiang L, Chen Y, Zhao Y, et al. Acetylation is crucial for p53-mediated ferroptosis and tumor suppression. Cell Rep. 2016;17:366–73.
Xie Y, Zhu S, Song X, Sun X, Fan Y, Liu J, et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep. 2017;20:1692–704.
Jennis M, Kung CP, Basu S, Budina-Kolomets A, Leu JI, Khaku S, et al. An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model. Genes Dev. 2016;30:918–30.
Tarangelo A, Magtanong L, Bieging-Rolett KT, Li Y, Ye J, Attardi LD, et al. p53 suppresses metabolic stress-induced ferroptosis in cancer cells. Cell Rep. 2018;22:569–75.
Hangauer MJ, Viswanathan VS, Ryan MJ, Bole D, Eaton JK, Matov A, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017;551:247–50.
Tsoi J, Robert L, Paraiso K, Galvan C, Sheu KM, Lay J, et al. Multi-stage differentiation defines melanoma subtypes with differential vulnerability to drug-induced iron-dependent oxidative stress. Cancer Cell. 2018;33:890–904.
Alvarez SW, Sviderskiy VO, Terzi EM, Papagiannakopoulos T, Moreira AL, Adams S, et al. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature. 2017;551:639–43.
Sarhan M, Land WG, Tonnus W, Hugo CP, Linkermann A. Origin and consequences of necroinflammation. Physiol Rev. 2018;98:727–80.
Lewerenz L, Ates G, Methner A, Conrad M, Maher P. Oxytosis/ferroptosis—(Re-)emerging roles for oxidative stress-dependent non-apoptotic cell death in diseases of the central nervous system. Front Neurosci. 2018;12:214.
Cardoso BR, Hare DJ, Bush AI, Roberts BR. Glutathione peroxidase 4: a new player in neurodegeneration? 63: Mol Psychiatry. 2017;22:328–335.
Friedmann Angeli JP, Conrad M. Selenium and GPX4, a vital symbiosis. Free Radic Biol Med. 2018; pii: S0891-5849(18)30104-7. https://doi.org/10.1016/j.freeradbiomed.2018.03.001. [Epub ahead of print]
Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell. 2018;172:409–22. e21
Green DR. An element of life. Cell. 2018;172:389–90.
Mulay SR, Linkermann A, Anders HJ. Necroinflammation in kidney disease. J Am Soc Nephrol. 2016;27:27–39.
Martin-Sanchez D, Ruiz-Andres O, Poveda J, Carrasco S, Cannata-Ortiz P, Sanchez-Nino MD, et al. Ferroptosis, but not necroptosis, is important in nephrotoxic folic acid-induced AKI. J Am Soc Nephrol JASN. 2017;28:218–29.
Martin-Sanchez D, Fontecha-Barriuso M, Carrasco S, Sanchez-Nino MD, Massenhausen AV, Linkermann A, et al. TWEAK and RIPK1 mediate a second wave of cell death during AKI. Proc Natl Acad Sci U S A. 2018;115:4182–4187.
Wenzel SE, Tyurina YY, Zhao J, St Croix CM, Dar HH, et al. PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell. 2017;171:628–41. e26
Huang HS, Chen CJ, Suzuki H, Yamamoto S, Chang WC. Inhibitory effect of phospholipid hydroperoxide glutathione peroxidase on the activity of lipoxygenases and cyclooxygenases. Prostaglandins Other Lipid Mediat. 1999;58:65–75.
Kulmacz RJ, Lands WEM . Peroxide tone in eicosanoid signaling. In: Forman HJ, Cadenas E, (eds.) Oxidative Stress and Signal Transduction. Boston, MA: Springer US: 1997. p 134–56. .
Kulmacz RJ, Lands WE. Requirements for hydroperoxide by the cyclooxygenase and peroxidase activities of prostaglandin H synthase. Prostaglandins. 1983;25:531–40.
Weitzel F, Wendel A. Selenoenzymes regulate the activity of leukocyte 5-lipoxygenase via the peroxide tone. J Biol Chem. 1993;268:6288–92.
Imai H, Narashima K, Arai M, Sakamoto H, Chiba N, Nakagawa Y. Suppression of leukotriene formation in RBL-2H3 cells that overexpressed phospholipid hydroperoxide glutathione peroxidase. J Biol Chem. 1998;273:1990–7.
Sakamoto H, Imai H, Nakagawa Y. Involvement of phospholipid hydroperoxide glutathione peroxidase in the modulation of prostaglandin D2 synthesis. J Biol Chem. 2000;275:40028–35.
Musee J, Marnett LJ. Prostaglandin H synthase-2-catalyzed oxygenation of 2-arachidonoylglycerol is more sensitive to peroxide tone than oxygenation of arachidonic acid. J Biol Chem. 2012;287:37383–94.
Chen CJ, Huang HS, Lin SB, Chang WC. Regulation of cyclooxygenase and 12-lipoxygenase catalysis by phospholipid hydroperoxide glutathione peroxidase in A431 cells. Prostaglandins Leukot Essent Fat Acids. 2000;62:261–8.
Chen CJ, Huang HS, Chang WC. Inhibition of arachidonate metabolism in human epidermoid carcinoma a431 cells overexpressing phospholipid hydroperoxide glutathione peroxidase. J Biomed Sci. 2002;9:453–9.
Schneider M, Wortmann M, Mandal PK, Arpornchayanon W, Jannasch K, Alves F, et al. Absence of glutathione peroxidase 4 affects tumor angiogenesis through increased 12/15-lipoxygenase activity. Neoplasia. 2010;12:254–63.
Sengupta A, Lichti UF, Carlson BA, Cataisson C, Ryscavage AO, Mikulec C, et al. Targeted disruption of glutathione peroxidase 4 in mouse skin epithelial cells impairs postnatal hair follicle morphogenesis that is partially rescued through inhibition of COX-2. J Invest Dermatol. 2013;133:1731–41.
Li Y, Maher P, Schubert D. A role for 12-lipoxygenase in nerve cell death caused by glutathione depletion. Neuron. 1997;19:453–63.
Jin G, Arai K, Murata Y, Wang S, Stins MF, Lo EH, et al. Protecting against cerebrovascular injury: contributions of 12/15-lipoxygenase to edema formation after transient focal ischemia. Stroke. 2008;39:2538–43.
van Leyen K, Kim HY, Lee SR, Jin G, Arai K, Lo EH. Baicalein and 12/15-lipoxygenase in the ischemic brain. Stroke. 2006;37:3014–8.
Brutsch SH, Wang CC, Li L, Stender H, Neziroglu N, Richter C, et al. Expression of inactive glutathione peroxidase 4 leads to embryonic lethality, and inactivation of the alox15 gene does not rescue such knock-in mice. Antioxid Redox Signal. 2015;22:281–93.
Brutsch SH, Rademacher M, Roth SR, Muller K, Eder S, Viertel D, et al. Male subfertility induced by heterozygous expression of catalytically inactive glutathione peroxidase 4 is rescued in vivo by systemic inactivation of the Alox15 gene. J Biol Chem. 2016;291:23578–23588.
Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA. 2016;113:E4966–75.
Latchoumycandane C, Marathe GK, Zhang R, McIntyre TM. Oxidatively truncated phospholipids are required agents of TNFalpha induced apoptosis. J Biol Chem. 2012.
Garg AD, Agostinis P. Cell death and immunity in cancer: from danger signals to mimicry of pathogen defense responses. Immunol Rev. 2017;280:126–148.
Acknowledgements
This work was funded by the Deutsche Forschungsgemeinschaft (DFG) CO 291/5-1, the Human Frontier Science Program (HFSP) RGP0013, the German Federal Ministry of Education and Research (BMBF) through the Joint Project Modelling ALS Disease In Vitro (MAIV, 01EK1611B) and the VIP + program NEUROPROTEKT (03VP04260).
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Proneth, B., Conrad, M. Ferroptosis and necroinflammation, a yet poorly explored link. Cell Death Differ 26, 14–24 (2019). https://doi.org/10.1038/s41418-018-0173-9
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DOI: https://doi.org/10.1038/s41418-018-0173-9
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