Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The role of iron and reactive oxygen species in cell death

Nature Chemical Biology volume 10, pages 9–17 (2014)Cite this article

Subjects

Abstract

The transition metal iron is essential for life, yet potentially toxic iron-catalyzed reactive oxygen species (ROS) are unavoidable in an oxygen-rich environment. Iron and ROS are increasingly recognized as important initiators and mediators of cell death in a variety of organisms and pathological situations. Here, we review recent discoveries regarding the mechanism by which iron and ROS participate in cell death. We describe the different roles of iron in triggering cell death, targets of iron-dependent ROS that mediate cell death and a new form of iron-dependent cell death termed ferroptosis. Recent advances in understanding the role of iron and ROS in cell death offer unexpected surprises and suggest new therapeutic avenues to treat cancer, organ damage and degenerative disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The role of iron in ROS metabolism.
Figure 2: Oxidative inactivation of essential enzymes and labile iron release can lead to death.
Figure 3: Involvement of ROS in apoptotic cell death.
Figure 4: The role of iron and ROS in necroptosis and ferroptosis.
Figure 5: Iron overload death in in absence of ROS in S. cerevisiae.
Figure 6: Small-molecule modulators of ROS- and iron-dependent death.

Similar content being viewed by others

References

  1. Frey, P.A. & Reed, G.H. The ubiquity of iron. ACS Chem. Biol. 7, 1477–1481 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Lambeth, J.D. & Neish, A.S. Nox enzymes and new thinking on reactive oxygen: a double-edged sword revisited. Annu. Rev. Pathol. doi:10.1146/annurev-pathol-012513-104651 (2013).

  3. Kell, D.B. Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases. BMC Med. Genomics 2, 2 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Petrat, F., de Groot, H., Sustmann, R. & Rauen, U. The chelatable iron pool in living cells: a methodically defined quantity. Biol. Chem. 383, 489–502 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Kurz, T., Eaton, J.W. & Brunk, U.T. The role of lysosomes in iron metabolism and recycling. Int. J. Biochem. Cell Biol. 43, 1686–1697 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Carlioz, A. & Touati, D. Isolation of superoxide dismutase mutants in Escherichia coli: is superoxide dismutase necessary for aerobic life? EMBO J. 5, 623–630 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Imlay, J.A. The molecular mechanisms and physiological consequences of oxidative stress: lessons from a model bacterium. Nat. Rev. Microbiol. 11, 443–454 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Flint, D.H., Tuminello, J.F. & Emptage, M.H. The inactivation of Fe-S cluster containing hydro-lyases by superoxide. J. Biol. Chem. 268, 22369–22376 (1993).

    CAS  PubMed  Google Scholar 

  9. Esposito, L.A., Melov, S., Panov, A., Cottrell, B.A. & Wallace, D.C. Mitochondrial disease in mouse results in increased oxidative stress. Proc. Natl. Acad. Sci. USA 96, 4820–4825 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Melov, S. et al. Mitochondrial disease in superoxide dismutase 2 mutant mice. Proc. Natl. Acad. Sci. USA 96, 846–851 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li, Y. et al. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat. Genet. 11, 376–381 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Brennan, A.M. et al. NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation. Nat. Neurosci. 12, 857–863 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Farrow, M.A. et al. Clostridium difficile toxin B–induced necrosis is mediated by the host epithelial cell NADPH oxidase complex. Proc. Natl. Acad. Sci. USA 110, 18674–18679 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Seaver, L.C. & Imlay, J.A. Alkyl hydroperoxide reductase is the primary scavenger of endogenous hydrogen peroxide in Escherichia coli. J. Bacteriol. 183, 7173–7181 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Park, S., You, X. & Imlay, J.A. Substantial DNA damage from submicromolar intracellular hydrogen peroxide detected in Hpx− mutants of Escherichia coli. Proc. Natl. Acad. Sci. USA 102, 9317–9322 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jang, S. & Imlay, J.A. Micromolar intracellular hydrogen peroxide disrupts metabolism by damaging iron-sulfur enzymes. J. Biol. Chem. 282, 929–937 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Jang, S. & Imlay, J.A. Hydrogen peroxide inactivates the Escherichia coli Isc iron-sulphur assembly system, and OxyR induces the Suf system to compensate. Mol. Microbiol. 78, 1448–1467 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Anjem, A. & Imlay, J.A. Mononuclear iron enzymes are primary targets of hydrogen peroxide stress. J. Biol. Chem. 287, 15544–15556 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sobota, J.M. & Imlay, J.A. Iron enzyme ribulose-5-phosphate 3-epimerase in Escherichia coli is rapidly damaged by hydrogen peroxide but can be protected by manganese. Proc. Natl. Acad. Sci. USA 108, 5402–5407 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Cvetkovic, A. et al. Microbial metalloproteomes are largely uncharacterized. Nature 466, 779–782 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Antunes, F., Cadenas, E. & Brunk, U.T. Apoptosis induced by exposure to a low steady-state concentration of H2O2 is a consequence of lysosomal rupture. Biochem. J. 356, 549–555 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hamacher-Brady, A. et al. Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production. J. Biol. Chem. 286, 6587–6601 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Seiler, A. et al. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 8, 237–248 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Heo, J.M. et al. A stress-responsive system for mitochondrial protein degradation. Mol. Cell 40, 465–480 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Madeo, F., Frohlich, E. & Frohlich, K.U. A yeast mutant showing diagnostic markers of early and late apoptosis. J. Cell Biol. 139, 729–734 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Braun, R.J. et al. Crucial mitochondrial impairment upon CDC48 mutation in apoptotic yeast. J. Biol. Chem. 281, 25757–25767 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Madeo, F. et al. Oxygen stress: a regulator of apoptosis in yeast. J. Cell Biol. 145, 757–767 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bartolome, F. et al. Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels. Neuron 78, 57–64 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Raimundo, N. et al. Mitochondrial stress engages E2F1 apoptotic signaling to cause deafness. Cell 148, 716–726 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chae, S. et al. A systems approach for decoding mitochondrial retrograde signaling pathways. Sci. Signal. 6, rs4 (2013).

    Article  CAS  PubMed  Google Scholar 

  31. Kagan, V.E. et al. Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors. Nat. Chem. Biol. 1, 223–232 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Ji, J. et al. Lipidomics identifies cardiolipin oxidation as a mitochondrial target for redox therapy of brain injury. Nat. Neurosci. 15, 1407–1413 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jiang, J. et al. Interplay between bax, reactive oxygen species production, and cardiolipin oxidation during apoptosis. Biochem. Biophys. Res. Commun. 368, 145–150 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ricci, J.E. et al. Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell 117, 773–786 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Huai, J. et al. TNFa-induced lysosomal membrane permeability (LMP) is downstream of MOMP and triggered by caspase-mediated p75 cleavage and ROS formation. J. Cell Sci. 126, 4015–4025 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Garcia-Perez, C. et al. Bid-induced mitochondrial membrane permeabilization waves propagated by local reactive oxygen species (ROS) signaling. Proc. Natl. Acad. Sci. USA 109, 4497–4502 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Degterev, A. et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 1, 112–119 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Linkermann, A. et al. Two independent pathways of regulated necrosis mediate ischemia-reperfusion injury. Proc. Natl. Acad. Sci. USA 110, 12024–12029 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Zhang, D.W. et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325, 332–336 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Vercammen, D. et al. Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J. Exp. Med. 187, 1477–1485 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shulga, N. & Pastorino, J.G. GRIM-19–mediated translocation of STAT3 to mitochondria is necessary for TNF-induced necroptosis. J. Cell Sci. 125, 2995–3003 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kim, Y.S., Morgan, M.J., Choksi, S. & Liu, Z.G. TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Mol. Cell 26, 675–687 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Yazdanpanah, B. et al. Riboflavin kinase couples TNF receptor 1 to NADPH oxidase. Nature 460, 1159–1163 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Xie, C. et al. Distinct roles of basal steady-state and induced H-ferritin in tumor necrosis factor–induced death in L929 cells. Mol. Cell. Biol. 25, 6673–6681 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dixon, S.J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yagoda, N. et al. RAS-RAF-MEK–dependent oxidative cell death involving voltage-dependent anion channels. Nature 447, 864–868 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yang, W.S. & Stockwell, B.R. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem. Biol. 15, 234–245 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gout, P.W., Buckley, A.R., Simms, C.R. & Bruchovsky, N. Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the xc− cystine transporter: a new action for an old drug. Leukemia 15, 1633–1640 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Murphy, T.H., Miyamoto, M., Sastre, A., Schnaar, R.L. & Coyle, J.T. Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. Neuron 2, 1547–1558 (1989).

    Article  CAS  PubMed  Google Scholar 

  50. Wolpaw, A.J. et al. Modulatory profiling identifies mechanisms of small molecule–induced cell death. Proc. Natl. Acad. Sci. USA 108, E771–E780 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Shaw, A.T. et al. Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress. Proc. Natl. Acad. Sci. USA 108, 8773–8778 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Siddiq, A. et al. Selective inhibition of hypoxia-inducible factor (HIF) prolyl-hydroxylase 1 mediates neuroprotection against normoxic oxidative death via HIF- and CREB-independent pathways. J. Neurosci. 29, 8828–8838 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Li, Y., Maher, P. & Schubert, D. A role for 12-lipoxygenase in nerve cell death caused by glutathione depletion. Neuron 19, 453–463 (1997).

    Article  CAS  PubMed  Google Scholar 

  54. Abeysinghe, R.D. et al. The environment of the lipoxygenase iron binding site explored with novel hydroxypyridinone iron chelators. J. Biol. Chem. 271, 7965–7972 (1996).

    Article  CAS  PubMed  Google Scholar 

  55. Tan, S., Schubert, D. & Maher, P. Oxytosis: A novel form of programmed cell death. Curr. Top. Med. Chem. 1, 497–506 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Zaman, K. et al. Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-1 and ATF-1/CREB and increased expression of glycolytic enzymes, p21(waf1/cip1), and erythropoietin. J. Neurosci. 19, 9821–9830 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Tan, S., Wood, M. & Maher, P. Oxidative stress induces a form of programmed cell death with characteristics of both apoptosis and necrosis in neuronal cells. J. Neurochem. 71, 95–105 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Tobaben, S. et al. Bid-mediated mitochondrial damage is a key mechanism in glutamate-induced oxidative stress and AIF-dependent cell death in immortalized HT-22 hippocampal neurons. Cell Death Differ. 18, 282–292 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Henke, N. et al. The plasma membrane channel ORAI1 mediates detrimental calcium influx caused by endogenous oxidative stress. Cell Death Dis. 4, e470 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Volpe, J.J., Kinney, H.C., Jensen, F.E. & Rosenberg, P.A. The developing oligodendrocyte: key cellular target in brain injury in the premature infant. Int. J. Dev. Neurosci. 29, 423–440 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sato, H. et al. Distribution of cystine/glutamate exchange transporter, system xc−, in the mouse brain. J. Neurosci. 22, 8028–8033 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hentze, M.W., Muckenthaler, M.U., Galy, B. & Camaschella, C. Two to tango: regulation of mammalian iron metabolism. Cell 142, 24–38 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Puccio, H. et al. Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat. Genet. 27, 181–186 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Eaton, J.W. & Qian, M. Molecular bases of cellular iron toxicity. Free Radic. Biol. Med. 32, 833–840 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Silva-Gomes, S. et al. Transcription factor NRF2 protects mice against dietary iron–induced liver injury by preventing hepatocytic cell death. J. Hepatol. doi:10.1016/j.jhep.2013.09.004 (2013).

  66. Torti, S.V. & Torti, F.M. Iron and cancer: more ore to be mined. Nat. Rev. Cancer 13, 342–355 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kruer, M.C. The neuropathology of neurodegeneration with brain iron accumulation. Int. Rev. Neurobiol. 110, 165–194 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lei, P. et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat. Med. 18, 291–295 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Duce, J.A. et al. Iron-export ferroxidase activity of b-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell 142, 857–867 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kaur, D. et al. Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease. Neuron 37, 899–909 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Guzman, J.N. et al. Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature 468, 696–700 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Allen, G.F., Toth, R., James, J. & Ganley, I.G. Loss of iron triggers PINK1/Parkin-independent mitophagy. EMBO Rep. doi:10.1038/embor.2013.168 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chen, Y. et al. Dexras1, a small GTPase, is required for glutamate-NMDA neurotoxicity. J. Neurosci. 33, 3582–3587 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Cheah, J.H. et al. NMDA receptor–nitric oxide transmission mediates neuronal iron homeostasis via the GTPase Dexras1. Neuron 51, 431–440 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Vaseva, A.V. et al. p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 149, 1536–1548 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zhang, X. & Lemasters, J.J. Translocation of iron from lysosomes to mitochondria during ischemia predisposes to injury after reperfusion in rat hepatocytes. Free Radic. Biol. Med. 63, 243–253 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Uchiyama, A. et al. Translocation of iron from lysosomes into mitochondria is a key event during oxidative stress–induced hepatocellular injury. Hepatology 48, 1644–1654 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Li, L., Chen, O.S., McVey Ward, D. & Kaplan, J. CCC1 is a transporter that mediates vacuolar iron storage in yeast. J. Biol. Chem. 276, 29515–29519 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Lin, H., Li, L., Jia, X., Ward, D.M. & Kaplan, J. Genetic and biochemical analysis of high iron toxicity in yeast: iron toxicity is due to the accumulation of cytosolic iron and occurs under both aerobic and anaerobic conditions. J. Biol. Chem. 286, 3851–3862 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Holmes-Hampton, G.P., Jhurry, N.D., McCormick, S.P. & Lindahl, P.A. Iron content of Saccharomyces cerevisiae cells grown under iron-deficient and iron-overload conditions. Biochemistry 52, 105–114 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Li, L., Bagley, D., Ward, D.M. & Kaplan, J. Yap5 is an iron-responsive transcriptional activator that regulates vacuolar iron storage in yeast. Mol. Cell. Biol. 28, 1326–1337 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Lee, Y.J. et al. Sphingolipid signaling mediates iron toxicity. Cell Metab. 16, 90–96 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Breslow, D.K. et al. Orm family proteins mediate sphingolipid homeostasis. Nature 463, 1048–1053 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kelso, G.F. et al. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J. Biol. Chem. 276, 4588–4596 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. McManus, M.J., Murphy, M.P. & Franklin, J.L. The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer's disease. J. Neurosci. 31, 15703–15715 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lowes, D.A., Webster, N.R., Murphy, M.P. & Galley, H.F. Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. Br. J. Anaesth. 110, 472–480 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wipf, P. et al. Mitochondrial targeting of selective electron scavengers: synthesis and biological analysis of hemigramicidin-TEMPO conjugates. J. Am. Chem. Soc. 127, 12460–12461 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Xun, Z. et al. Targeting of XJB-5–131 to mitochondria suppresses oxidative DNA damage and motor decline in a mouse model of Huntington's disease. Cell Rep. 2, 1137–1142 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. DeNicola, G.M. et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106–109 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Son, J. et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Maddocks, O.D. et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493, 542–546 (2013).

    Article  CAS  PubMed  Google Scholar 

  92. Trachootham, D., Alexandre, J. & Huang, P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat. Rev. Drug Discov. 8, 579–591 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Pei, S. et al. Targeting aberrant glutathione metabolism to eradicate human acute myelogenous leukemia cells. J. Biol. Chem. doi:10.1074/jbc.M113.511170 (2013).

  94. Trachootham, D. et al. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by b-phenylethyl isothiocyanate. Cancer Cell 10, 241–252 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Raj, L. et al. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 475, 231–234 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Dolma, S., Lessnick, S.L., Hahn, W.C. & Stockwell, B.R. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 3, 285–296 (2003).

    Article  CAS  PubMed  Google Scholar 

  97. Diehn, M. et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780–783 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kohanski, M.A., Dwyer, D.J., Hayete, B., Lawrence, C.A. & Collins, J.J. A common mechanism of cellular death induced by bactericidal antibiotics. Cell 130, 797–810 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Liu, Y. & Imlay, J.A. Cell death from antibiotics without the involvement of reactive oxygen species. Science 339, 1210–1213 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhang, S. et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat. Med. 18, 1639–1642 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Cochemé, H.M. et al. Measurement of H2O2 within living Drosophila during aging using a ratiometric mass spectrometry probe targeted to the mitochondrial matrix. Cell Metab. 13, 340–350 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Albrecht, S.C., Barata, A.G., Grosshans, J., Teleman, A.A. & Dick, T.P. In vivo mapping of hydrogen peroxide and oxidized glutathione reveals chemical and regional specificity of redox homeostasis. Cell Metab. 14, 819–829 (2011).

    Article  CAS  PubMed  Google Scholar 

  103. Au-Yeung, H.Y., Chan, J., Chantarojsiri, T. & Chang, C.J. Molecular imaging of labile iron(II) pools in living cells with a turn-on fluorescent probe. J. Am. Chem. Soc. 135, 15165–15173 (2013).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a K99 Pathway to Independence Award from the National Cancer Institute to S.J.D. (1K99CA166517-01). B.R.S. is an Early Career Scientist of the Howard Hughes Medical Institute and is supported by grants from the US National Institutes of Health (5R01CA097061, 5R01GM085081 and R01CA161061) and New York State Stem Cell Science.

Author information

Author notes

  1. Scott J Dixon

    Present address: Present address: Department of Biology, Stanford University, Stanford, California, USA.,

Authors and Affiliations

  1. Department of Biological Sciences, Columbia University, New York, New York, USA

    Scott J Dixon & Brent R Stockwell

  2. Department of Chemistry, Columbia University, New York, New York, USA

    Brent R Stockwell

  3. Department of Systems Biology, Columbia University, New York, New York, USA

    Brent R Stockwell

  4. Howard Hughes Medical Institute, Columbia University, New York, New York, USA

    Brent R Stockwell

Authors
  1. Scott J Dixon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brent R Stockwell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Scott J Dixon or Brent R Stockwell.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dixon, S., Stockwell, B. The role of iron and reactive oxygen species in cell death. Nat Chem Biol 10, 9–17 (2014). https://doi.org/10.1038/nchembio.1416

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.1416

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing