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Review
. 2020 Jun 20;9(6):1505.
doi: 10.3390/cells9061505.

Ferroptosis and Cancer: Mitochondria Meet the "Iron Maiden" Cell Death

Anna Martina Battaglia  1 , Roberta Chirillo  1 , Ilenia Aversa  1 , Alessandro Sacco  1 , Francesco Costanzo  1   2 , Flavia Biamonte  1   3
Affiliations
Review

Ferroptosis and Cancer: Mitochondria Meet the "Iron Maiden" Cell Death

Anna Martina Battaglia et al. Cells. .

Abstract

Ferroptosis is a new type of oxidative regulated cell death (RCD) driven by iron-dependent lipid peroxidation. As major sites of iron utilization and master regulators of oxidative metabolism, mitochondria are the main source of reactive oxygen species (ROS) and, thus, play a role in this type of RCD. Ferroptosis is, indeed, associated with severe damage in mitochondrial morphology, bioenergetics, and metabolism. Furthermore, dysregulation of mitochondrial metabolism is considered a biochemical feature of neurodegenerative diseases linked to ferroptosis. Whether mitochondrial dysfunction can, per se, initiate ferroptosis and whether mitochondrial function in ferroptosis is context-dependent are still under debate. Cancer cells accumulate high levels of iron and ROS to promote their metabolic activity and growth. Of note, cancer cell metabolic rewiring is often associated with acquired sensitivity to ferroptosis. This strongly suggests that ferroptosis may act as an adaptive response to metabolic imbalance and, thus, may constitute a new promising way to eradicate malignant cells. Here, we review the current literature on the role of mitochondria in ferroptosis, and we discuss opportunities to potentially use mitochondria-mediated ferroptosis as a new strategy for cancer therapy.

Keywords: ROS; cancer; cell death; ferroptosis; iron; mitochondria.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Regulatory metabolic pathways of ferroptosis. Metabolic pathways are divided into enzymatic (left panel) and non-enzymatic (right panel) mechanisms as well as into canonical (green dots) and non-canonical (orange dots). (1) Lipid metabolism pathway: AA and other PUFAs derived from lipid bilayers are metabolized by ACSL4 and LPCAT and then oxidized by LOXs to produce L-ROS. (2) FSP1-CoQ10-NADPH pathway: in plasma membrane, FSP1 reduces CoQ10 to ubiquinol which, in turn, blocks lipid peroxidation. (3) Mevalonate pathway: acetyl-CoA is converted to HMG-CoA by HMGCR. HMG-CoA is reduced to mevalonate which, in turn, is converted to IPP. As a result, a selenocysteine residue is added to catalytic center of GPX4. This event leads to GPX4 activation and ferroptosis inhibition. IPP also generates CoQ10, thus entering into the FSP1 pathway. (4) GPX4 pathway: GPX4 catalyzes the reduction of lipid peroxides thus preventing ferroptosis. (5) Glutaminolysis pathway: Extracellular glutamine, internalized through SLC1A5, is converted to glutamate by GLS. (6) Cystine deprivation-induced (CDI) ferroptosis pathways: amino acid antiporter system xc− (composed by SLC3A2 and SLC7A11 subunits) mediates the exchange of extracellular cystine and intracellular glutamate. Cystine is converted in cysteine which, in turn, contributes to GSH production. Cystine deprivation triggers ferroptosis through GSH depletion. (7) Iron metabolism pathway: Fe3+-loaded TF is imported through TFR1. Fe3+ is converted in Fe2+ by STEAP3 and released into cytoplasm via DMT1. Fe2+ participates in Fenton Reaction, producing L-ROS and causing ferroptosis. (8) Ferritinophagy: Ferritin stores iron and reduces Fe2+ in Fe3+, limiting the Fenton Reaction. The NCOA4 binds ferritin mediating its autophagic degradation in a process called ferritinophagy. This mechanism promotes ferroptosis. Abbreviation used: AA, arachidonic acid; PUFAs, polyunsaturated fatty acids; ACSL4, long-chain-fatty-acid—CoA ligase 4; LPCAT, lyso-phosphatidylcholine acyltransferase; LOXs, lipoxygenase; L-ROS, lipid reactive oxygen species, PE, phosphatidylethanolamine; FSP1, ferroptosis-suppressor-protein 1 (also known as AIFM2); CoQ10, coenzyme Q10 (also known as ubiquinone); CoA, coenzyme A; HMGCR, 3-Hydroxy-3-Methylglutaryl-CoA Reductase; IPP, isopentenyl pyrophosphate; GPX4, glutathione peroxidase 4; SLC1A5, Solute Carrier Family 1 Member 5; GLS, glutaminase; CDI, Cystine deprivation-induced; SLC3A2, Solute Carrier Family 3 Member 2; SLC7A11, Solute Carrier Family 7 Member 11; GSH, glutathione; TF, transferrin; TFR1, transferrin receptor; STEAP3, STEAP3 Metalloreductase; DMT1, divalent metal transporter 1; L-ROS, lipid reactive oxygen species; NCOA4, nuclear receptor coactivator 4.
Figure 2
Figure 2
Iron crossroads from cytosol to mitochondria. Cytosolic iron metabolism: (1) TFR1 internalizes Fe3+-loaded TF through an endocytosis-mediated mechanism. (2) Fe2+ uptake is carried out by the transmembrane permeable channel DMT1. (3) NTBI enters cytoplasm through the zinc transporter ZIP 8/14 upon its reduction in Fe2+ mediated by PRNP. (4) Fe3+-loaded TF and NTBI are released in the endosome by TFR1 and ZIP8/14, respectively. STEAP3 converts Fe3+ to Fe2+ which, in turn, enters the cytoplasm via DMT1. After internalization, all these carriers are recycled to the cell surface. (5) GRX3 and BOLA2 constitute a heterotrimeric complex involved in the CIA system for (Fe–S) cluster formation. (6) PCBP1/2 iron chaperones bind iron and deliver it via direct protein–protein interaction with PHD2, FIH1, DOHH, and ferritin, in a process known as metallation. (7) LIP is a pool of free and redox-active iron which promotes ROS generation through a Fenton Reaction. (8) Ferritin is an iron-storage protein with ferroxidase activity, able to convert toxic Fe2+ in non-toxic Fe3+, thus preventing a Fenton Reaction. (9) IRPs coordinate iron homeostasis at the post-transcriptional level. IRP1/2 blocks degradation of TFR1 mRNA and inhibits the translation of both ferritin subunits, FtH and FtL, and FPN. (10) FPN exports iron in the extracellular space; its activity is decreased by hepcidin that directly binds to FPN. Mitochondrial iron metabolism: (11) LIP released by lysosomes is rapidly taken up by MCU and internalized into mitochondria. (12) Mfrn1/2 imports Fe2+ from the intermembrane space of the mitochondria to the mitochondrial matrix. (13) VDAC2/3 mediates iron mitochondrial uptake. (14) Endosomal iron is delivered in mitochondria through the so-called “kiss and run” mechanism. (15) FECH forms an oligomeric complex with ABCB10 to synergistically promote mitochondrial iron import. (16) Fe2+ participates to Fenton Reaction-generating mitoROS. (17) FtMt, an H-type ferritin, is involved in mitochondrial iron storage. (18) PPIX incorporates iron to generate heme and mediates ISC export. (19) Mitochondrial iron can even enter the ISC assembly machinery, responsible for the maturation of all cellular (Fe–S) clusters; then, it can be mobilized to OXPHOS complex I/II/III. (20) NEET iron–sulfur proteins transfer their 2Fe–2S clusters to an apo-acceptor protein and CIA system. (21) CISD1, also called mitoNEET, regulates mitochondrial iron export. (22) ABCB7/8 are mitochondrial Fe–S cluster export proteins. (23) FLVCR1 mediates mitochondrial heme export. Abbreviations used: TFR1, transferrin receptor; TF, transferrin; DMT1, divalent metal transporter 1; NTBI, non-transferrin bound iron; ZIP 8/14, zinc finger iron proteins 8/14; PRNP, prion protein; STEAP3, six-transmembrane epithelial antigen of prostate 3; GRX3, glutathione-dependent oxidoreductase; BOLA2, BolA family member 2; CIA, cytosolic iron–sulfur cluster assembly; PCBP1/2, poly(RC) binding protein 1/2; PHD2, prolyl hydroxylase domain-containing protein 2; FIH1, factor inhibiting HIF-1; DOHH, deoxyhypusine hydroxylase; LIP, labile iron pool; ROS, reactive oxygen species; IRP, iron-responsive element-binding proteins; FtH, ferritin heavy chain; FtL, ferritin light chain; FPN, ferroportin; MCU, mitochondrial calcium uniporter; Mfrn1/2, mitoferrin 1/2; VDAC2/3, voltage-dependent anion-selective channel 2/3; FECH, ferrochelatase; ABCB10/7/8, ATP-binding cassette transporter 10/7/8; mitoROS, mitochondrial reactive oxygen species; FtMt, mitochondrial ferritin; PPIX, protoporphyrin IX; ISC, iron–sulfur (Fe–S) clusters; OXPHOS, oxidative phosphorylation; NEET proteins, also known as CDGSH iron sulfur domain 3; CISD1, CDGSH iron sulfur domain 1; ABCB7/8, ATP binding cassette subfamily b member 7/8; FLVCR1, feline leukemia virus subgroup C cellular receptor 1.
Figure 3
Figure 3
Mitochondrial metabolic processes in ferroptosis. (1) Iron uptake via Mfrn1/2 increases LIP amount, promoting mitoROS generation through Fenton Reaction. (2) BID triggers ferroptosis through BAX and BAK activation and the consequent dysregulation of ΔΨm. (3) ACSF2 regulates activation of fatty acids derived from carnitine shuttle mechanism, providing the specific lipid precursor for β-oxidation. (4) VDAC2/3 imports Fe2+ into mitochondria. Fe2+ contributes to enhance LIP which, in turn, generates mitoROS. (5) MnSOD converts superoxide anion (O2−) from ETC to hydrogen peroxide (H2O2) which takes part into Fenton Reaction, thus promoting ferroptosis. (6) CISD1 regulates mitochondrial iron export acting as ferroptosis suppressor. (7) FtMt prevents Fenton Reaction through iron-storage and ferroxidase activities. (8) LONP1 maintains mitochondrial integrity, preventing ferroptosis induction. (9) ACSL4, LPCAT, and LOXs activate lipid peroxidation, driving ferroptosis. (10) CS regulates fatty acid synthesis through the release of CoA, a precursor for β-oxidation, thus inducing ferroptosis. (11) Glutamine is converted to glutamate by the mitochondrial isoform GLS2. Glutamate is converted in α-KG by GDH and GOT/GPT enzymes, thus providing fuel for TCA cycle and lipid biosynthesis. Abbreviations used: Mfrn1/2, mitoferrin 1/2; LIP, labile iron pool; mitoROS, mitochondrial reactive oxygen species; BID, BH3 interacting-domain death agonist; BAX, Bcl-2-associated X protein (also known as bcl-2-like protein 4); BAK, Bcl-2 homologous antagonist killer; ACSF2, acyl-CoA synthetase family member 2; VDAC2/3, voltage-dependent anion channels 2/3; MnSOD, mitochondrial superoxide dismutase; ETC, electron transport chain; CISD1, CDGSH Iron Sulfur Domain 1; FtMt, mitochondrial ferritin; LONP1, lon peptidase 1; ACSL4, long-chain-fatty-acid—CoA ligase 4; LPCAT, lyso-phosphatidylcholine acyltransferase; LOXs, lipoxygenase; AA, arachidonic acid; PE, phosphatidylethanolamine; CPT1/2, carnitine palmitoyltransferase 1/2;CS, citrate synthase; CoA, coenzyme A; GLS1/2, glutaminase 1/2; α-KG: alpha-ketoglutarate; GDH, glutamate dehydrogenase; GOT, glutamic oxaloacetic transaminase; GTP, glutamic pyruvic transaminase; TCA cycle (tricarboxylic acid cycle); AOA, amino-oxyacetic acid.
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References

    1. Han C., Liu Y., Dai R., Ismail N., Su W., Li B. Ferroptosis and its potential role in human diseases. Front. Pharmacol. 2020;11:239. doi: 10.3389/fphar.2020.00239. - DOI - PMC - PubMed
    1. Dixon S.J., Stockwell B.R. The hallmarks of ferroptosis. Annu. Rev. Cancer Biol. 2019;3:35–54. doi: 10.1146/annurev-cancerbio-030518-055844. - DOI
    1. Li Y., Feng D., Wang Z., Zhao Y., Sun R., Tian D., Liu D., Zhang F., Ning S., Yao J., et al. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ. 2019;26:2284–2299. doi: 10.1038/s41418-019-0299-4. - DOI - PMC - PubMed
    1. Belaidi A.A., Bush A.I. Iron neurochemistry in Alzheimer’s disease and Parkinson’s disease: Targets for therapeutics. J. Neurochem. 2016;139:179–197. doi: 10.1111/jnc.13425. - DOI - PubMed
    1. Ma S., Henson E.S., Chen Y., Gibson S.B. Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells. Cell Death Dis. 2016 doi: 10.1038/cddis.2016.208. - DOI - PMC - PubMed