Skip to main content

Advertisement

Log in

Ferroptosis, a Recent Defined Form of Critical Cell Death in Neurological Disorders

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Ferroptosis is a recently defined form of cell death with the involvement of iron and reactive oxygen species (ROS), which is distinct from apoptosis, autophagy and other forms of cell death. Emerging evidence suggested that iron accumulation and lipid peroxidation can be discovered in various neurological diseases, accompanied with reduction of glutathione (GSH) and glutathione peroxidase 4 (GPX4). In addition, ferroptotic inhibitors have been shown to protect neurons, and recover the cognitive function in disease animal models. This review summarizes the mechanisms underlying ferroptosis and reviews the contributions of ferroptosis in neurodegenerative diseases (i.e. Alzheimer’s disease and Parkinson’s disease), traumatic brain injury, as well as hemorrhagic and ischemic stroke, to provide the current understanding of this novel form of cell death in neurological disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Abeyawardhane DL, Fernandez RD, Murgas CJ, Heitger DR, Forney AK, Crozier MK, Lucas HR (2018) Iron redox chemistry promotes antiparallel oligomerization of alpha-Synuclein. J Am Chem Soc 140(15):5028–5032

    Article  CAS  PubMed  Google Scholar 

  • Abeysinghe RD, Roberts PJ, Cooper CE, MacLean KH, Hider RC, Porter JB (1996) The environment of the lipoxygenase iron binding site explored with novel hydroxypyridinone iron chelators. J Biol Chem 271(14):7965–7972

    Article  CAS  PubMed  Google Scholar 

  • Adeghate E, Parvez SH (2000) Nitric oxide and neuronal and pancreatic beta cell death. Toxicology 153(1–3):143–156

    Article  CAS  PubMed  Google Scholar 

  • Agrawal S, Fox J, Thyagarajan B, Fox JH (2018) Brain mitochondrial iron accumulates in Huntington’s disease, mediates mitochondrial dysfunction, and can be removed pharmacologically. Free Radic Biol Med 120:317–329

    Article  CAS  PubMed  Google Scholar 

  • Ahmad S, Elsherbiny NM, Haque R, Khan MB, Ishrat T, Shah ZA, Khan MM, Ali M, Jamal A, Katare DP, Liou GI, Bhatia K (2014) Sesamin attenuates neurotoxicity in mouse model of ischemic brain stroke. Neurotoxicology 45:100–110

    Article  CAS  PubMed  Google Scholar 

  • Auchere F, Santos R, Planamente S, Lesuisse E, Camadro JM (2008) Glutathione-dependent redox status of frataxin-deficient cells in a yeast model of Friedreich’s ataxia. Hum Mol Genet 17(18):2790–2802

    Article  CAS  PubMed  Google Scholar 

  • Ayton S, Lei P (2014) Nigral iron elevation is an invariable feature of Parkinson’s disease and is a sufficient cause of neurodegeneration. Biomed Res Int 2014:581256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ayton S, Lei P, Bush AI (2013) Metallostasis in Alzheimer’s disease. Free Radic Biol Med 62:76–89

    Article  CAS  PubMed  Google Scholar 

  • Ayton S, Zhang M, Roberts BR, Lam LQ, Lind M, McLean C, Bush AI, Frugier T, Crack PJ, Duce JA (2014) Ceruloplasmin and beta-amyloid precursor protein confer neuroprotection in traumatic brain injury and lower neuronal iron. Free Radic Biol Med 69:331–337

    Article  CAS  PubMed  Google Scholar 

  • Ayton S, Lei P, Hare DJ, Duce JA, George JL, Adlard PA, McLean C, Rogers JT, Cherny RA, Finkelstein DI, Bush AI (2015a) Parkinson’s disease iron deposition caused by nitric oxide-induced loss of beta-amyloid precursor protein. J Neurosci 35(8):3591–3597

    Article  CAS  PubMed  Google Scholar 

  • Ayton S, Faux NG, Bush AI (2015b) Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE. Nat Commun 6:6760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ayton S, Lei P, Bush AI (2015c) Biometals and their therapeutic implications in Alzheimer’s disease. Neurotherapeutics 12(1):109–120

    Article  CAS  PubMed  Google Scholar 

  • Babu GN, Kumar A, Chandra R, Puri SK, Singh RL, Kalita J, Misra UK (2008) Oxidant-antioxidant imbalance in the erythrocytes of sporadic amyotrophic lateral sclerosis patients correlates with the progression of disease. Neurochem Int 52(6):1284–1289

    Article  CAS  PubMed  Google Scholar 

  • Back SA, Gan X, Li Y, Rosenberg PA, Volpe JJ (1998) Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion. J Neurosci 18(16):6241–6253

    Article  CAS  PubMed  Google Scholar 

  • Baenziger O, Martin E, Steinlin M, Good M, Largo R, Burger R, Fanconi S, Duc G, Buchli R, Rumpel H et al (1993) Early pattern recognition in severe perinatal asphyxia: a prospective MRI study. Neuroradiology 35(6):437–442

    Article  CAS  PubMed  Google Scholar 

  • Barradas MA, Jeremy JY, Kontoghiorghes GJ, Mikhailidis DP, Hoffbrand AV, Dandona P (1989) Iron chelators inhibit human platelet aggregation, thromboxane A2 synthesis and lipoxygenase activity. FEBS Lett 245(1–2):105–109

    Article  CAS  PubMed  Google Scholar 

  • Bayir H, Kagan VE, Tyurina YY, Tyurin V, Ruppel RA, Adelson PD, Graham SH, Janesko K, Clark RS, Kochanek PM (2002) Assessment of antioxidant reserves and oxidative stress in cerebrospinal fluid after severe traumatic brain injury in infants and children. Pediatr Res 51(5):571–578

    Article  PubMed  Google Scholar 

  • Belarbi K, Cuvelier E, Destee A, Gressier B, Chartier-Harlin MC (2017) NADPH oxidases in Parkinson’s disease: a systematic review. Mol Neurodegener 12(1):84

    Article  PubMed  PubMed Central  Google Scholar 

  • Brault S, Martinez-Bermudez AK, Roberts J 2nd, Cui QL, Fragoso G, Hemdan S, Liu HN, Gobeil F Jr, Quiniou C, Kermorvant-Duchemin E, Lachance C, Almazan G, Varma DR, Chemtob S (2004) Cytotoxicity of the E(2)-isoprostane 15-E(2t)-IsoP on oligodendrocyte progenitors. Free Radic Biol Med 37(3):358–366

    Article  CAS  PubMed  Google Scholar 

  • Ceschin R, Lee VK, Schmithorst V, Panigrahy A (2015) Regional vulnerability of longitudinal cortical association connectivity: associated with structural network topology alterations in preterm children with cerebral palsy. Neuroimage Clin 9:322–337

    Article  PubMed  PubMed Central  Google Scholar 

  • Chi L, Ke Y, Luo C, Gozal D, Liu R (2007) Depletion of reduced glutathione enhances motor neuron degeneration in vitro and in vivo. Neuroscience 144(3):991–1003

    Article  CAS  PubMed  Google Scholar 

  • Chmatalova Z, Vyhnalek M, Laczo J, Hort J, Pospisilova R, Pechova M, Skoumalova A (2017) Relation of plasma selenium and lipid peroxidation end products in patients with Alzheimer’s disease. Physiol Res 66(6):1049–1056

    CAS  PubMed  Google Scholar 

  • Codazzi F, Hu A, Rai M, Donatello S, Salerno Scarzella F, Mangiameli E, Pelizzoni I, Grohovaz F, Pandolfo M (2016) Friedreich ataxia-induced pluripotent stem cell-derived neurons show a cellular phenotype that is corrected by a benzamide HDAC inhibitor. Hum Mol Genet 25(22):4847–4855

    CAS  PubMed  Google Scholar 

  • Connor JR, Menzies SL, Martin SMS, Mufson EJ (1992) A histochemical study of iron, transferrin, and ferritin in Alzheimer’s diseased brains. J Neurosci Res 31(1):75–83

    Article  CAS  PubMed  Google Scholar 

  • Conrad M, Kagan VE, Bayir H, Pagnussat GC, Head B, Traber MG, Stockwell BR (2018) Regulation of lipid peroxidation and ferroptosis in diverse species. Genes Dev 32(9–10):602–619

    Article  CAS  PubMed  Google Scholar 

  • Crapper McLachlan DR, Dalton AJ, Kruck TP, Bell MY, Smith WL, Kalow W, Andrews DF (1991) Intramuscular desferrioxamine in patients with Alzheimer’s disease. Lancet 337(8753):1304–1308

    Article  CAS  PubMed  Google Scholar 

  • Davies P, Moualla D, Brown DR (2011) Alpha-synuclein is a cellular ferrireductase. PLoS One 6(1):e15814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Di Fonzo A, Ronchi D, Gallia F, Cribiu FM, Trezzi I, Vetro A, Della Mina E, Limongelli I, Bellazzi R, Ricca I, Micieli G, Fassone E, Rizzuti M, Bordoni A, Fortunato F, Salani S, Mora G, Corti S, Ceroni M, Bosari S, Zuffardi O, Bresolin N, Nobile-Orazio E, Comi GP (2014) Lower motor neuron disease with respiratory failure caused by a novel MAPT mutation. Neurology 82(22):1990–1998

    Article  CAS  PubMed  Google Scholar 

  • Di Pietro V, Lazzarino G, Amorini AM, Tavazzi B, D’Urso S, Longo S, Vagnozzi R, Signoretti S, Clementi E, Giardina B, Lazzarino G, Belli A (2014) Neuroglobin expression and oxidant/antioxidant balance after graded traumatic brain injury in the rat. Free Radic Biol Med 69:258–264

    Article  CAS  PubMed  Google Scholar 

  • Dietrich RB, Bradley WG Jr (1988) Iron accumulation in the basal ganglia following severe ischemic-anoxic insults in children. Radiology 168(1):203–206

    Article  CAS  PubMed  Google Scholar 

  • Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B, Stockwell BR (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Do Van B, Gouel F, Jonneaux A, Timmerman K, Gele P, Petrault M, Bastide M, Laloux C, Moreau C, Bordet R, Devos D, Devedjian JC (2016) Ferroptosis, a newly characterized form of cell death in Parkinson’s disease that is regulated by PKC. Neurobiol Dis 94:169–178

    Article  CAS  PubMed  Google Scholar 

  • Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, Irmler M, Beckers J, Aichler M, Walch A, Prokisch H, Trumbach D, Mao G, Qu F, Bayir H, Fullekrug J, Scheel CH, Wurst W, Schick JA, Kagan VE, Angeli JP, Conrad M (2017) ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol 13(1):91–98

    Article  CAS  PubMed  Google Scholar 

  • Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, Leong SL, Perez KA, Johanssen TJ, Greenough MA, Cho H-H, Galatis D, Moir RD, Masters CL, Mclean C, Tanzi RE, Cappai R, Barnham KJ, Ciccotosto GD, Rogers JT, Bush AI (2010) Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer’s disease. Cell 142(6):857–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duce JA, Wong BX, Durham H, Devedjian JC, Smith DP, Devos D (2017) Post translational changes to alpha-synuclein control iron and dopamine trafficking; a concept for neuron vulnerability in Parkinson’s disease. Mol Neurodegener 12(1):45

    Article  PubMed  PubMed Central  Google Scholar 

  • Feng G, Zhang Z, Bao Q, Zhang Z, Zhou L, Jiang J, Li S (2014) Protective effect of chinonin in MPTP-induced C57BL/6 mouse model of Parkinson’s disease. Biol Pharm Bull 37(8):1301–1307

    Article  CAS  PubMed  Google Scholar 

  • Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A, Eggenhofer E, Basavarajappa D, Radmark O, Kobayashi S, Seibt T, Beck H, Neff F, Esposito I, Wanke R, Forster H, Yefremova O, Heinrichmeyer M, Bornkamm GW, Geissler EK, Thomas SB, Stockwell BR, O’Donnell VB, Kagan VE, Schick JA, Conrad M (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 16(12):1180–1191

    Article  CAS  PubMed  Google Scholar 

  • Fu AL, Dong ZH, Sun MJ (2006) Protective effect of N-acetyl-L-cysteine on amyloid beta-peptide-induced learning and memory deficits in mice. Brain Res 1109(1):201–206

    Article  CAS  PubMed  Google Scholar 

  • Gao M, Monian P, Quadri N, Ramasamy R, Jiang X (2015) Glutaminolysis and transferrin regulate Ferroptosis. Mol Cell 59(2):298–308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gaschler MM, Andia AA, Liu H, Csuka JM, Hurlocker B, Vaiana CA, Heindel DW, Zuckerman DS, Bos PH, Reznik E, Ye LF, Tyurina YY, Lin AJ, Shchepinov MS, Chan AY, Peguero-Pereira E, Fomich MA, Daniels JD, Bekish AV, Shmanai VV, Kagan VE, Mahal LK, Woerpel KA, Stockwell BR (2018) FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol 14(5):507–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghosh D, Levault KR, Brewer GJ (2014) Relative importance of redox buffers GSH and NAD (P) H in age-related neurodegeneration and Alzheimer disease-like mouse neurons. Aging Cell 13(4):631–640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Golko-Perez S, Amit T, Bar-Am O, Youdim MB, Weinreb O (2017) A novel iron chelator-radical scavenger ameliorates motor dysfunction and improves life span and mitochondrial biogenesis in SOD1(G93A) ALS mice. Neurotox Res 31(2):230–244

    Article  CAS  PubMed  Google Scholar 

  • Hambright WS, Fonseca RS, Chen L, Na R, Ran Q (2017) Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol 12:8–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanson LR, Roeytenberg A, Martinez PM, Coppes VG, Sweet DC, Rao RJ, Marti DL, Hoekman JD, Matthews RB, Frey WH 2nd, Panter SS (2009) Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke. J Pharmacol Exp Ther 330(3):679–686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hider RC, Kong XL (2011) Glutathione: a key component of the cytoplasmic labile iron pool. Biometals 24(6):1179–1187

    Article  CAS  PubMed  Google Scholar 

  • Ingold I, Aichler M, Yefremova E, Roveri A, Buday K, Doll S, Tasdemir A, Hoffard N, Wurst W, Walch A, Ursini F, Friedmann Angeli JP, Conrad M (2015) Expression of a catalytically inactive mutant form of glutathione peroxidase 4 (Gpx4) confers a dominant-negative effect in male fertility. J Biol Chem 290(23):14668–14678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, Roveri A, Peng X, Porto Freitas F, Seibt T, Mehr L, Aichler M, Walch A, Lamp D, Jastroch M, Miyamoto S, Wurst W, Ursini F, Arner ESJ, Fradejas-Villar N, Schweizer U, Zischka H, Friedmann Angeli JP, Conrad M (2018) Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell 172(3):409–422 e421

    Article  CAS  PubMed  Google Scholar 

  • Ito K, Eguchi Y, Imagawa Y, Akai S, Mochizuki H, Tsujimoto Y (2017) MPP+ induces necrostatin-1- and ferrostatin-1-sensitive necrotic death of neuronal SH-SY5Y cells. Cell Death Discov 3:17013

    Article  PubMed  PubMed Central  Google Scholar 

  • Izzet T, Osman K, Ethem U, Nihat Y, Ramazan K, Mustafa D, Hafize U, Riza KA, Birsen A, Habibe G, Seval A, Gonul S (2005) Oxidative stress in portal hypertension-induced rats with particular emphasis on nitric oxide and trace metals. World J Gastroenterol 11(23):3570–3573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson WM, Wilson-Delfosse AL, Mieyal JJ (2012) Dysregulation of glutathione homeostasis in neurodegenerative diseases. Nutrients 4(10):1399–1440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, Dar HH, Liu B, Tyurin VA, Ritov VB, Kapralov AA, Amoscato AA, Jiang J, Anthonymuthu T, Mohammadyani D, Yang Q, Proneth B, Klein-Seetharaman J, Watkins S, Bahar I, Greenberger J, Mallampalli RK, Stockwell BR, Tyurina YY, Conrad M, Bayir H (2017) Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 13(1):81–90

    Article  CAS  PubMed  Google Scholar 

  • Kehrer JP (2000) The Haber-Weiss reaction and mechanisms of toxicity. Toxicology 149(1):43–50

    Article  CAS  PubMed  Google Scholar 

  • Khalaf S, Ahmad AS, Chamara K, Dore S (2018) Unique properties associated with the brain penetrant iron chelator HBED reveal remarkable beneficial effects after brain trauma. J Neurotrauma

  • Klepac N, Relja M, Klepac R, Hecimovic S, Babic T, Trkulja V (2007) Oxidative stress parameters in plasma of Huntington’s disease patients, asymptomatic Huntington’s disease gene carriers and healthy subjects: a cross-sectional study. J Neurol 254(12):1676–1683

    Article  CAS  PubMed  Google Scholar 

  • Klivenyi P, Andreassen OA, Ferrante RJ, Dedeoglu A, Mueller G, Lancelot E, Bogdanov M, Andersen JK, Jiang D, Beal MF (2000) Mice deficient in cellular glutathione peroxidase show increased vulnerability to malonate, 3-nitropropionic acid, and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. J Neurosci 20(1):1–7

    Article  CAS  PubMed  Google Scholar 

  • Koeppen AH, Morral JA, McComb RD, Feustel PJ (2011) The neuropathology of late-onset Friedreich’s ataxia. Cerebellum 10(1):96–103

    Article  PubMed  PubMed Central  Google Scholar 

  • Kondo Y, Ogawa N, Asanuma M, Ota Z, Mori A (1995) Regional differences in late-onset iron deposition, ferritin, transferrin, astrocyte proliferation, and microglial activation after transient forebrain ischemia in rat brain. J Cereb Blood Flow Metab 15(2):216–226

    Article  CAS  PubMed  Google Scholar 

  • Kuhn H, Banthiya S, van Leyen K (2015) Mammalian lipoxygenases and their biological relevance. Biochim Biophys Acta 1851(4):308–330

    Article  CAS  PubMed  Google Scholar 

  • Kwan JY, Jeong SY, Van Gelderen P, Deng HX, Quezado MM, Danielian LE, Butman JA, Chen L, Bayat E, Russell J, Siddique T, Duyn JH, Rouault TA, Floeter MK (2012) Iron accumulation in deep cortical layers accounts for MRI signal abnormalities in ALS: correlating 7 tesla MRI and pathology. PLoS One 7(4):e35241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lane DJR, Ayton S, Bush AI (2018) Iron and Alzheimer’s disease: an update on emerging mechanisms. J Alzheimers Dis 64(s1):S379–S395

    Article  CAS  PubMed  Google Scholar 

  • Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, Wong BX, Adlard PA, Cherny RA, Lam LQ, Roberts BR, Volitakis I, Egan GF, McLean CA, Cappai R, Duce JA, Bush AI (2012) Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med 18(2):291–295

    Article  CAS  PubMed  Google Scholar 

  • Lei P, Ayton S, Appukuttan AT, Moon S, Duce JA, Volitakis I, Cherny R, Wood SJ, Greenough M, Berger G, Pantelis C, McGorry P, Yung A, Finkelstein DI, Bush AI (2017) Lithium suppression of tau induces brain iron accumulation and neurodegeneration. Mol Psychiatry 22(3):396–406

    Article  CAS  PubMed  Google Scholar 

  • Li X, Lei P, Tuo Q, Ayton S, Li QX, Moon S, Volitakis I, Liu R, Masters CL, Finkelstein DI, Bush AI (2015) Enduring elevations of hippocampal amyloid precursor protein and iron are features of beta-amyloid toxicity and are mediated by tau. Neurotherapeutics 12(4):862–873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Q, Han X, Lan X, Gao Y, Wan J, Durham F, Cheng T, Yang J, Wang Z, Jiang C, Ying M, Koehler RC, Stockwell BR, Wang J (2017) Inhibition of neuronal ferroptosis protects hemorrhagic brain. JCI Insight 2(7):e90777

    Article  PubMed  PubMed Central  Google Scholar 

  • Li QQ, Li Q, Jia JN, Liu ZQ, Zhou HH, Mao XY (2018) 12/15 lipoxygenase: a crucial enzyme in diverse types of cell death. Neurochem Int 118:34–41

    Article  CAS  PubMed  Google Scholar 

  • Liu L, Huang W, Wang J, Song H, Cen J, Ji B (2017) Anthraquinone derivative exerted hormetic effect on the apoptosis in oxygen-glucose deprivation-induced PC12 cells via ERK and Akt activated Nrf2/HO-1 signaling pathway. Chem Biol Interact 262:1–11

    Article  CAS  PubMed  Google Scholar 

  • Ma MW, Wang J, Zhang Q, Wang R, Dhandapani KM, Vadlamudi RK, Brann DW (2017) NADPH oxidase in brain injury and neurodegenerative disorders. Mol Neurodegener 12(1):7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mathews CE, Leiter EH (1999) Constitutive differences in antioxidant defense status distinguish alloxan-resistant and alloxan-susceptible mice. Free Radic Biol Med 27(3–4):449–455

    Article  CAS  PubMed  Google Scholar 

  • Mehdiratta M, Kumar S, Hackney D, Schlaug G, Selim M (2008) Association between serum ferritin level and perihematoma edema volume in patients with spontaneous intracerebral hemorrhage. Stroke 39(4):1165–1170

    Article  CAS  PubMed  Google Scholar 

  • Napoli E, Taroni F, Cortopassi GA (2006) Frataxin, iron-sulfur clusters, heme, ROS, and aging. Antioxid Redox Signal 8(3–4):506–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333(24):1581–1587

    Article  Google Scholar 

  • Perez de la Ossa N, Sobrino T, Silva Y, Blanco M, Millan M, Gomis M, Agulla J, Araya P, Reverte S, Serena J, Davalos A (2010) Iron-related brain damage in patients with intracerebral hemorrhage. Stroke 41(4):810–813

    Article  CAS  PubMed  Google Scholar 

  • Raven EP, Lu PH, Tishler TA, Heydari P, Bartzokis G (2013) Increased iron levels and decreased tissue integrity in hippocampus of Alzheimer’s disease detected in vivo with magnetic resonance imaging. J Alzheimers Dis 37(1):127–136

    Article  CAS  PubMed  Google Scholar 

  • Shintoku R, Takigawa Y, Yamada K, Kubota C, Yoshimoto Y, Takeuchi T, Koshiishi I, Torii S (2017) Lipoxygenase-mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3. Cancer Sci 108(11):2187–2194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Skouta R, Dixon SJ, Wang J, Dunn DE, Orman M, Shimada K, Rosenberg PA, Lo DC, Weinberg JM, Linkermann A, Stockwell BR (2014) Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc 136(12):4551–4556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascon S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD (2017) Ferroptosis: a regulated cell death Nexus linking metabolism, redox biology, and disease. Cell 171(2):273–285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tuo QZ, Lei P, Jackman KA, Li XL, Xiong H, Li XL, Liuyang ZY, Roisman L, Zhang ST, Ayton S, Wang Q, Crouch PJ, Ganio K, Wang XC, Pei L, Adlard PA, Lu YM, Cappai R, Wang JZ, Liu R, Bush AI (2017) Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry 22(11):1520–1530

    Article  CAS  PubMed  Google Scholar 

  • Van Hoecke M, Prigent-Tessier A, Bertrand N, Prevotat L, Marie C, Beley A (2005) Apoptotic cell death progression after photothrombotic focal cerebral ischaemia: effects of the lipophilic iron chelator 2,2′-dipyridyl. Eur J Neurosci 22(5):1045–1056

    Article  PubMed  Google Scholar 

  • Vinceti M, Chiari A, Eichmuller M, Rothman KJ, Filippini T, Malagoli C, Weuve J, Tondelli M, Zamboni G, Nichelli PF, Michalke B (2017) A selenium species in cerebrospinal fluid predicts conversion to Alzheimer’s dementia in persons with mild cognitive impairment. Alzheimers Res Ther 9(1):100

    Article  PubMed  PubMed Central  Google Scholar 

  • Welin AK, Svedin P, Lapatto R, Sultan B, Hagberg H, Gressens P, Kjellmer I, Mallard C (2007) Melatonin reduces inflammation and cell death in white matter in the mid-gestation fetal sheep following umbilical cord occlusion. Pediatr Res 61(2):153–158

    Article  CAS  PubMed  Google Scholar 

  • Wenzel SE, Tyurina YY, Zhao J, Croix CMS, Dar HH, Mao G, Tyurin VA, Anthonymuthu TS, Kapralov AA, Amoscato AA, Mikulska-Ruminska K, Shrivastava IH, Kenny EM, Yang Q, Rosenbaum JC, Sparvero LJ, Emlet DR, Wen X, Minami Y, Qu F, Watkins SC, Holman TR, VanDemark AP, Kellum JA, Bahar I, Bayir H, Kagan VE (2017) PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell 171(3):628–641 e626

    Article  CAS  PubMed  Google Scholar 

  • Wullner U, Loschmann PA, Schulz JB, Schmid A, Dringen R, Eblen F, Turski L, Klockgether T (1996) Glutathione depletion potentiates MPTP and MPP+ toxicity in nigral dopaminergic neurones. Neuroreport 7(4):921–923

    Article  CAS  PubMed  Google Scholar 

  • Xu J, Wang H, Ding K, Zhang L, Wang C, Li T, Wei W, Lu X (2014) Luteolin provides neuroprotection in models of traumatic brain injury via the Nrf2-ARE pathway. Free Radic Biol Med 71:186–195

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto A, Shin R-W, Hasegawa K, Naiki H, Sato H, Yoshimasu F, Kitamoto T (2002) Iron (III) induces aggregation of hyperphosphorylated tau and its reduction to iron (II) reverses the aggregation: implications in the formation of neurofibrillary tangles of Alzheimer’s disease. J Neurochem 82(5):1137–1147

    Article  CAS  PubMed  Google Scholar 

  • Yang WS, Stockwell BR (2008) Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol 15(3):234–245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR (2016) Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA 113(34):E4966–E4975

    Article  CAS  PubMed  Google Scholar 

  • Yigitkanli K, Pekcec A, Karatas H, Pallast S, Mandeville E, Joshi N, Smirnova N, Gazaryan I, Ratan RR, Witztum JL, Montaner J, Holman TR, Lo EH, van Leyen K (2013) Inhibition of 12/15-lipoxygenase as therapeutic strategy to treat stroke. Ann Neurol 73(1):129–135

    Article  CAS  PubMed  Google Scholar 

  • Yoo MH, Gu X, Xu XM, Kim JY, Carlson BA, Patterson AD, Cai H, Gladyshev VN, Hatfield DL (2010) Delineating the role of glutathione peroxidase 4 in protecting cells against lipid hydroperoxide damage and in Alzheimer’s disease. Antioxid Redox Signal 12(7):819–827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang ZH, Wu QY, Zheng R, Chen C, Chen Y, Liu Q, Hoffmann PR, Ni JZ, Song GL (2017) Selenomethionine mitigates cognitive decline by targeting both tau hyperphosphorylation and Autophagic clearance in an Alzheimer’s disease mouse model. J Neurosci 37(9):2449–2462

    Article  PubMed  Google Scholar 

  • Zhang YH, Wang DW, Xu SF, Zhang S, Fan YG, Yang YY, Guo SQ, Wang S, Guo T, Wang ZY, Guo C (2018) Alpha-lipoic acid improves abnormal behavior by mitigation of oxidative stress, inflammation, ferroptosis, and tauopathy in P301S Tau transgenic mice. Redox Biol 14:535–548

    Article  CAS  PubMed  Google Scholar 

  • Zhou ZD, Tan EK (2017) Iron regulatory protein (IRP)-iron responsive element (IRE) signaling pathway in human neurodegenerative diseases. Mol Neurodegener 12(1):75

    Article  PubMed  PubMed Central  Google Scholar 

  • Zille M, Karuppagounder SS, Chen Y, Gough PJ, Bertin J, Finger J, Milner TA, Jonas EA, Ratan RR (2017) Neuronal death after hemorrhagic stroke in vitro and in vivo shares features of Ferroptosis and necroptosis. Stroke 48(4):1033–1043

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors declare no conflict of interest. This work was supported by funds from the National Natural Science Foundation of China (81722016, 91632115, and 81571236).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Peng Lei.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, Jr., Tuo, Qz. & Lei, P. Ferroptosis, a Recent Defined Form of Critical Cell Death in Neurological Disorders. J Mol Neurosci 66, 197–206 (2018). https://doi.org/10.1007/s12031-018-1155-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-018-1155-6

Keywords

Navigation