Ferroptosis: regulated cell death

Abstract

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.

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

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