Letter to the editor: iron, apoptosis, and ferroptosis
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LETTER TO THE EDITOR
Letter to the editor: iron, apoptosis, and ferroptosis Andrew J. Ghio1
© Springer Science+Business Media, LLC, part of Springer Nature 2020
To the editor A unique chemistry led to the evolutionary selection of iron for a wide range of fundamental cell functions, and the availability of this particular metal has become essential for almost every form of life. Iron concentrations in the environment were initially inadequate to meet the requirements for life and this necessitated the development of defined pathways to acquire critical metal. Concurrently, ironcatalyzed generation of radicals presented a potential for oxidative stress demanding that iron homeostasis be tightly controlled. Therefore, iron import, storage, and export are carefully regulated, and life exists at the precise interface between iron-deficiency and -sufficiency. Following an absolute iron-deficiency (e.g. anti-transferrin receptor antibodies and exposure to extracellular chelators), there is obstruction of the cell cycle at the S phase, engagement of MAP kinases, caspases, and proto-oncogene proteins, and initiation of a regulated cell death recognized as apoptosis [1]. More recently, ferroptosis regulated cell death was discovered. The definition of ferroptosis included cell death which was distinct from apoptosis, iron-dependent, and characterized by an accumulation of lipid peroxides [2]. In ferroptosis, it was suggested that accumulated iron catalyzed hydroxyl radical which, along with activation of enzymic pathways, resulted in elevated cell levels of lipid peroxides and cell denaturation. Ferroptosis was first described following cell exposure to erastin which was postulated to inhibit the cystine/glutamate antiporter leading to glutathione depletion, inactivation of glutathione peroxidase 4 (GPX4), an accumulation of lipid peroxides, and cell death [3]. An alternative explanation of the association between ferroptosis and disrupted iron homeostasis, the true hallmark feature of this pathway for regulated cell death, is proposed * Andrew J. Ghio [email protected] 1
US Environmental Protection Agency, Human Studies Facility, 104 Mason Farm Road, Chapel Hill, NC 27599−7315, USA
by other investigation. Ferroptosis has been repeatedly described in cells exposed to compounds and substances recognized chemically to form coordination (or chelation) complexes with iron and diseases following such exposures. These compounds and substances are numerous and include: microbials, endotoxin, particles and fibers, environmental pollutants (e.g. polychlorinated biphenyls, dioxin, and paraquat), toxins and venoms, anthracyclines, bleomycin, antibiotics, phenols and polyphenols, catecholamines, polychlorinated aromatic hydrocarbons, 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine, naphthoquinones, benzopyrene, tetrazolium salts, fatty acids, and lipoic acid. Exposure to these compounds and substances results in both a cell accumulation and a concurrent, functional deficiency of iron [4, 5]. Dependent on molecular weight, lipid so
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