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Ferroptosis: regulated cell death

Ivana Čepelak
Ivana Čepelak
, 
Slavica Dodig
Slavica Dodig
 and 
Daniela Čepelak Dodig
Daniela Čepelak Dodig
   | Jun 29, 2020
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Article Category: Original article
Published Online: Jun 29, 2020
Page range: 99 - 109
Received: Nov 01, 2019
Accepted: May 01, 2020
DOI: https://doi.org/10.2478/aiht-2020-71-3366
Keywords
© 2020 Ivana Čepelak et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

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
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

Some forms of regulated cell death and their properties

Cell type death Definition Morphological (and biochemical) features References
Apoptosis Apoptosis is a prevailing form of RCD that requires activation of caspases leading to DNA fragmentation without loss of plasma membrane integrity. It can be extrinsic and intrinsic. Membrane blebbing, cell shrinkage, retraction pseudopods, reduction of cellular and nuclear volume, nuclear fragmentation, chromatin condensation, apoptotic body formation (activation of caspases, e.g. CASP2, CASP8, CASP3, oligonucleosomal DNA fragmentation, cytochrome c release altered Bc1-2 family protein expression and activation) 6, 8, 9
Ferroptosis Ferroptosis is a form of cell death caused by iron-dependent lipid peroxidation and L-ROS accumulation. Normal spherical cells-lack of rupture and blebbing of the plasma membrane, rounding up of the cell, small mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria cristae, as well as outer mitochondrial membrane rupture, normal nuclear size (L-ROS accumulation, activation of MAPKs, inhibition of system Xc- with decreased cystine uptake, GSH depletion and increased NADPH oxidation, inhibition GPX4, release of AA mediators (e.g. 11-HETE and 15-HETE). 8, 9, 10
Pyroptosis Pyroptosis is a form of lytic cell death that occurs in inflammatory cells in response to proinflammatory stimuli. Inflammasome activation membrane rupture, cell swelling/cell oedema and lysis, pore-induced intracellular traps, DNA fragmentation, nuclear condensation (DAMP release-e.g.HMGB1, ATP), dependent on caspase 1 and 7, proinflammatory cytokine release. 9, 10
Necroptosis Necroptosis is a programmed form of necrosis, a modality of RCD that is activated by RIPK1 and requires RIPK3-dependent phosphorilation of MLKL. Plasma membrane rupture, cell swelling and lysis, organelle swelling, moderate chromatin condensation (ATP decline, DAMPs release, activation of RIPK1, RIPK3 and MLKL, PARP1 hyperactivation). 6, 8, 10, 11
Parthanatos Parthanatos is a PARP1-dependent RCD that is activated by oxidative stress-induced DNA damage and chromatinolysis. Cell swelling and lysis, DNA fragmentation, nuclear condensation, release of mitochondrial apoptosis-inducing factor [excessive activation of PARP1, caspase-independent NAD+ and ATP depletion, accumulation of poly ADPribose (PAR) polymers, AIFM1 release from mitochondria to nucleus]. 6,9
Autophagy- dependent cell death Autophagy-dependent cell death is a type of RCD dependent on autophagy machinery and/or components of autophagy. Autophagic vacuolisation, lack of cell membrane changes, lack of chromatin condensation, accumulation of double-membraned autophagic vacuoles, increased lysosomal activity, MAP1LC3B-I, MAP1LC3-II (or LC3B-I, LC3B-II) conversion, substrate degradation (e.g. p62). 6, 8, 9, 10
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