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Ferroptosis: the greasy side of cell death José Pedro Friedmann-Angeli, Sayuri Miyamoto, and Almut Schulze Chem. Res. Toxicol., Just Accepted Manuscript • DOI: 10.1021/acs.chemrestox.8b00349 • Publication Date (Web): 17 Jan 2019 Downloaded from http://pubs.acs.org on January 17, 2019
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Chemical Research in Toxicology
Ferroptosis: the greasy side of cell death
José Pedro Friedmann Angeli1*; Sayuri Miyamoto2; Almut Schulze3 1 - Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, 97080 Würzburg, Germany 2 - Departamento de Bioquímica, Instituto de Química , Universidade de São Paulo , São Paulo , Brazil 3 - Theodor-Boveri-Institute, Biocenter, University of Würzburg, 97074, Würzburg, Germany. *correspondence to
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Abstract Ferroptosis is a form of cell death that requires phospholipid peroxidation and has attracted increased attention, both as a means to eradicate tumors resistant to standard chemotherapy and for its potential contribution to tissue damage such as in ischemia/reperfusion. The centre stage taken by phospholipid peroxidation in ferroptosis is highlighted by recent discoveries that demonstrate an intricate regulation of both the metabolism of polyunsaturated fatty acids as well as mechanisms leading to their oxidation. These metabolic steps converge at the point of ferroptosis execution through mechanisms that are now only starting to be understood. In this short review we provide and appraisal of some of the recent advances in the understanding of the ferroptosis process and also provide some perspectives of where this knowledge could take us.
Ferroptosis For a long period of time, researchers have recognized that cells can die in distinct ways and were arbitrarily divided into controlled and uncontrolled forms of cell death, termed apoptosis and necrosis, respectively. Recent years, however, have revealed that forms of cell death previously believed to be of an accidental nature are in fact also tightly regulated1. This means that distinct defined metabolic and molecular regulatory nodes exist that determine cellular viability. Yet it should also be noted that not all of the reported pathways of cell death have been shown to be relevant in vivo and, consequently, their contribution to physiological and pathological situations might be limited. Among the different pathways that have received considerable attention during the last couple of years is ferroptosis. The term ferroptosis has been initially coined in a 2012 study by Dixon et al2., where the authors characterized a series of small molecules that were able to specifically trigger cell death in cancer cells carrying an oncogenic mutation of RAS (rat sarcoma) gene. At the molecular level, one of these small molecules, named Erastin, triggered cell death by the specific inhibition of the amino acid antiporter known as system Xc-. System Xc- is responsible for import of cystine, the oxidized form of cysteine, at the expense of the release of one molecule of glutamate3. Under specific conditions, such as in cell culture exposed to ambient oxygen tension, cystine becomes the sole source of cysteine and inhibition of system Xc- leads to a rapid depletion of the intracellular cysteine pool4. Cells devoid of cysteine are unable to maintain the intracellular pool of the most critical antioxidant, namely glutathione (GSH), and succumb to what was initially termed a “catastrophic” cell death caused by the accumulation of lipid derived reactive oxygen species (ROS)2. Consistent with the requirement of enzymatic systems to mediate the antioxidant function of GSH5, further studies have identified glutathione peroxidase 4 (GPX4)6-
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to be responsible for the pro-survival effect of GSH. This notion is reminiscent from mouse
studies showing that animals devoid of glutathione synthesis die at almost the same embryonic stage as GPX4 KO animals9. Together, these early studies provide what is now the backbone of our current knowledge regarding the process of ferroptosis10. Yet it has also to be noted that the process of cell death induced by cysteine starvation had already been recognized, and studied, previously in neuronal model systems exposed to high concentrations of glutamate11. In this system, the process of cell death has been named oxytosis, which also showed the hallmarks of ferroptosis, namely inhibition of cystine import, GSH depletion, and a detrimental accumulation of lipid derived ROS or lipid peroxidation11. Thus, these initial studies unequivocally describe the central function of phospholipid peroxidation as an essential element driving ferroptotic cell death.
Lipid peroxidation Phospholipid peroxidation or autoxidation is an unavoidable consequence of aerobic life. The chemistry of this process is a series of well-documented chemical reactions and particular credit has to be given to work performed in the lab of Ned Porter and his collaborators (reviewed in12) for elucidating this intriguing process. Lipid peroxidation is triggered by any species sufficiently reactive to abstract a hydrogen atom from the bis-allylic position of a polyunsaturated fatty acid (PUFA). These reactive groups include hydroxyl, alcoxyl, and hydroperoxyl radicals. This step initiates a free radical chain reaction, in which the pentadienyl radical reacts with molecular oxygen to generate a peroxyl radicals capable of propagating the chain reaction by abstracting a hydrogen atom from an adjacent PUFA. The process of phospholipid peroxidation can be considered an autocatalytic process, as the formed hydroperoxides can undergo fragmentation at the O-O bond, resulting in the formation of radicals able to initiate a new chain reaction. The fragmentation of peroxidic O–O bonds can be induced by heat, UV light, and low-valent transition metals such as iron (in the Fe2+state), in what is generally referred to as the Fenton reaction. Remarkably cellular proteins are also capable of oxidizing lipid substrates even in a stereospecific manner, although this reaction takes place without the presence of a free peroxyl intermediate13. Enzymes capable of oxidizing cellular lipids include lipoxygenases (ALOX), cyclooxygenases (COX) and some members of the cytochrome P450 (CYP) family of proteins. Particularly important for ferroptosis is the action of lipoxygenases that are able to generate lipid hydroperoxides that can feed directly into the autocatalytic process, through the fragmentation of the peroxide OO bond, as described above. The relevance of peroxidation is widespread and spans from industrial hydrocarbons to biological membranes – therefore intensive work has been carried
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out to interfere with this process14. Here, it is important to mention radical trapping antioxidants, which are molecules able to block the propagation of the peroxidation reaction. Inhibition of the propagation step is feasible mostly due to its very slow kinetics, typically showing propagation constant (kp) values from
