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Review
. 2020 Jun 29;71(2):99-109.
doi: 10.2478/aiht-2020-71-3366. Print 2020 Jun 1.

Ferroptosis: regulated cell death

Ivana Čepelak  1 , Slavica Dodig  1 , Daniela Čepelak Dodig  2
Affiliations
Review

Ferroptosis: regulated cell death

Ivana Čepelak et al. Arh Hig Rada Toksikol. .

Abstract
in English, Croatian

Ferroptosis is a recently identified form of regulated cell death that differs from other known forms of cell death morphologically, biochemically, and genetically. The main properties of ferroptosis are free redox-active iron and consequent iron-dependent peroxidation of polyunsaturated fatty acids in cell membrane phospholipids, which results in the accumulation of lipid-based reactive oxygen species due to loss of glutathione peroxidase 4 activity. Ferroptosis has increasingly been associated with neurodegenerative diseases, carcinogenesis, stroke, intracerebral haemorrhage, traumatic brain injury, and ischemia-reperfusion injury. It has also shown a significant therapeutic potential in the treatment of cancer and other diseases. This review summarises current knowledge about and the mechanisms that regulate ferroptosis.

Feroptoza je nedavno identificirani oblik regulirane stanične smrti koji se od ostalih poznatih oblika stanične smrti razlikuje morfološki, biokemijski i genetski. Glavna svojstva feroptoze uključuju slobodno redoks aktivno željezo i posljedičnu, o željezu ovisnu, peroksidaciju polinezasićenih masnih kiselina u fosfolipidima staničnih membrana te gubitak aktivnosti glutation peroksidaze 4, što rezultira akumulacijom lipidnih, reaktivnih kisikovih spojeva. Feroptoza se sve više povezuje s raznim bolestima kao što su neurodegenerativne bolesti, karcinom, moždani udar, intracerebralna krvarenja, traumatične ozljede mozga i ishemijsko-reperfuzijska ozljeda. Također je pokazan značajan terapijski potencijal u liječenju raka i drugih bolesti. Ovaj pregled sažima trenutačne spoznaje i mehanizme koji reguliraju feroptozu.

Keywords: glutathione peroxidase 4; iron; lipid peroxidation; reactive oxygen species; system Xc−.

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Figures

Figure 1
Figure 1
Proposed cellular mechanisms of ferroptosis. Ferroptosis occurs when the reduction of PL-PUFA (PE)-OOH via GPX4 is insufficient to prevent iron-mediated L-ROS accumulation. An important cysteine supply route for GSH synthesis is the import of cystine via the antiporter system Xc- (1). An additional or alternative cysteine route is transsulphuration (1a). GSSG is reversed into GSH with the catalytic action of NADPH-dependent GR (2) generated in the penthose phosphate patway (2a). GSH is a cofactor of the GPX4 enzyme that prevents the accumulation of PL-PUFA(PE)-OOH by converting them to PL-PUFA(PE)-OH (3), and in the process of GPX4 maturation participates IPP from the mevalonate pathway (3a). Free redox active iron is involved in the formation of L-ROS from membrane PL-PUFA(PE) through the Fenton reaction and oxidation by15-LOX-1 (4). ACSL4 and LPCAT3 enzymes are involved in the formation of PL-PUFA (PE) (4a). AA – arachidonic acid; ACSL4 – acyl-CoA synthetase long chain family member 4; AdA – adrenic acid; GPX4 – glutathione peroxidase; GR – glutathione reductase; GSH – glutathione reduced form; GSSG – glutathione disulfide; IPP – isopentenyl pyrophosphate; LIP – labile iron pool; 15-LOX-1 – 15-lipooxygenase-1; LPCAT3-- lysophosphatidylcholine acyltransferase; L-ROS – lipid reactive oxygen species;PE – phosphatidylethanolamine; NADP – nicotinamide adenine dinucleotide phosphate; NADPH – reduced nicotinamide adenine dinucleotide phosphate; PL-PUFA(PE)-OH – lipid alcohol; PL-PUFA(PE)-OOH – PUFA-containing phospholipid hydroperoxides; PL-PUFA(PE) – PUFA-containing phospholipids; PUFA – polyunsaturated fatty acid; Se – selenocysteine
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