Ferritin heavy chain protects the developing wing from reactive oxygen species and ferroptosis

English version

Autoři: Simone Mumbauer ^aff001; Justine Pascual ^aff001; Irina Kolotuev ^aff002; Fisun Hamaratoglu ^aff001
Působiště autorů: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland ^aff001; Electron Microscopy Facility, University of Lausanne, Lausanne, Switzerland ^aff002; School of Biosciences, Cardiff University, Cardiff, United Kingdom ^aff003
Vyšlo v časopise: Ferritin heavy chain protects the developing wing from reactive oxygen species and ferroptosis. PLoS Genet 15(9): e32767. doi:10.1371/journal.pgen.1008396
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008396

Souhrn

The interplay between signalling pathways and metabolism is crucial for tissue growth. Yet, it remains poorly understood. Here, we studied the consequences of modulating iron metabolism on the growth of Drosophila imaginal discs. We find that reducing the levels of the ferritin heavy chain in the larval wing discs leads to drastic growth defects, whereas light chain depletion causes only minor defects. Mutant cell clones for the heavy chain lack the ability to compete against Minute mutant cells. Reactive oxygen species (ROS) accumulate in wing discs with reduced heavy chain levels, causing severe mitochondrial defects and ferroptosis. Preventing ROS accumulation alleviates some of the growth defects. We propose that the increased expression of ferritin in hippo mutant cells may protect against ROS accumulation.

Klíčová slova:

Apoptosis – Drosophila melanogaster – Mitochondria – Reactive oxygen species – RNA interference – Ferritin – Mutant genotypes

Zdroje

1. Anderson GJ, Frazer DM. Current understanding of iron homeostasis. Am J Clin Nutr. 2017;106(Suppl 6):1559S–66S. doi: 10.3945/ajcn.117.155804 29070551

2. Lill R. Function and biogenesis of iron-sulphur proteins. Nature. 2009;460(7257):831–8. doi: 10.1038/nature08301 19675643

3. Hamburger AE, West AP, Hamburger ZA, Hamburger P, Bjorkman PJ. Crystal structure of a secreted insect ferritin reveals a symmetrical arrangement of heavy and light chains. J Mol Biol. 2005;349(3):558–69. doi: 10.1016/j.jmb.2005.03.074 15896348

4. Tang X, Zhou B. Iron homeostasis in insects: Insights from Drosophila studies. IUBMB Life. 2013;65(10):863–72. doi: 10.1002/iub.1211 24078394

5. Arosio P, Carmona F, Gozzelino R, Maccarinelli F, Poli M. The importance of eukaryotic ferritins in iron handling and cytoprotection. Biochem J. 2015;472(1):1–15. doi: 10.1042/BJ20150787 26518749

6. Marchetti A, Parker MS, Moccia LP, Lin EO, Arrieta AL, Ribalet F, et al. Ferritin is used for iron storage in bloom-forming marine pennate diatoms. Nature. 2009;457(7228):467–70. doi: 10.1038/nature07539 19037243

7. Galay RL, Umemiya-Shirafuji R, Bacolod ET, Maeda H, Kusakisako K, Koyama J, et al. Two kinds of ferritin protect ixodid ticks from iron overload and consequent oxidative stress. PLoS One. 2014;9(3):e90661. doi: 10.1371/journal.pone.0090661 24594832

8. Bulvik BE, Berenshtein E, Meyron-Holtz EG, Konijn AM, Chevion M. Cardiac protection by preconditioning is generated via an iron-signal created by proteasomal degradation of iron proteins. PLoS One. 2012;7(11):e48947. doi: 10.1371/journal.pone.0048947 23155431

9. Li S. Identification of iron-loaded ferritin as an essential mitogen for cell proliferation and postembryonic development in Drosophila. Cell Res. 2010;20(10):1148–57. doi: 10.1038/cr.2010.102 20628369

10. Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, et al. Oncogenic Signaling Pathways in The Cancer Genome Atlas. Cell. 2018;173(2):321–37.e10. doi: 10.1016/j.cell.2018.03.035 29625050

11. Hariharan IK. Organ Size Control: Lessons from Drosophila. Dev Cell. 2015;34(3):255–65. doi: 10.1016/j.devcel.2015.07.012 26267393

12. Piccolo S, Dupont S, Cordenonsi M. The biology of YAP/TAZ: hippo signaling and beyond. Physiol Rev. 2014;94(4):1287–312. doi: 10.1152/physrev.00005.2014 25287865

13. Halder G, Camargo FD. The hippo tumor suppressor network: from organ size control to stem cells and cancer. Cancer Res. 2013;73(21):6389–92. doi: 10.1158/0008-5472.CAN-13-2392 24022648

14. Fulford A, Tapon N, Ribeiro PS. Upstairs, downstairs: spatial regulation of Hippo signalling. Curr Opin Cell Biol. 2018;51:22–32. doi: 10.1016/j.ceb.2017.10.006 29154163

15. Huang J, Wu S, Barrera J, Matthews K, Pan D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell. 2005;122(3):421–34. doi: 10.1016/j.cell.2005.06.007 16096061

16. Pascual J, Jacobs J, Sansores-Garcia L, Natarajan M, Zeitlinger J, Aerts S, et al. Hippo Reprograms the Transcriptional Response to Ras Signaling. Dev Cell. 2017;42(6):667–80.e4. doi: 10.1016/j.devcel.2017.08.013 28950103

17. Atkins M, Potier D, Romanelli L, Jacobs J, Mach J, Hamaratoglu F, et al. An Ectopic Network of Transcription Factors Regulated by Hippo Signaling Drives Growth and Invasion of a Malignant Tumor Model. Curr Biol. 2016;26(16):2101–13. doi: 10.1016/j.cub.2016.06.035 27476594

18. Missirlis F, Kosmidis S, Brody T, Mavrakis M, Holmberg S, Odenwald WF, et al. Homeostatic mechanisms for iron storage revealed by genetic manipulations and live imaging of Drosophila ferritin. Genetics. 2007;177(1):89–100. doi: 10.1534/genetics.107.075150 17603097

19. González-Morales N, Mendoza-Ortíz M, Blowes LM, Missirlis F, Riesgo-Escovar JR. Ferritin Is Required in Multiple Tissues during Drosophila melanogaster Development. PLoS One. 2015;10(7):e0133499. doi: 10.1371/journal.pone.0133499 26192321

20. Gutiérrez L, Zubow K, Nield J, Gambis A, Mollereau B, Lázaro FJ, et al. Biophysical and genetic analysis of iron partitioning and ferritin function in Drosophila melanogaster. Metallomics. 2013;5(8):997–1005. doi: 10.1039/c3mt00118k 23771129

21. Morata G, Ripoll P. Minutes: mutants of drosophila autonomously affecting cell division rate. Dev Biol. 1975;42(2):211–21. doi: 10.1016/0012-1606(75)90330-9 1116643

22. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell. 2017;171(2):273–85. doi: 10.1016/j.cell.2017.09.021 28985560

23. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–72. doi: 10.1016/j.cell.2012.03.042 22632970

24. Bannai S, Tsukeda H, Okumura H. Effect of antioxidants on cultured human diploid fibroblasts exposed to cystine-free medium. Biochem Biophys Res Commun. 1977;74(4):1582–8. doi: 10.1016/0006-291x(77)90623-4 843380

25. Hirschhorn T, Stockwell BR. The development of the concept of ferroptosis. Free Radic Biol Med. 2018.

26. Feng H, Stockwell BR. Unsolved mysteries: How does lipid peroxidation cause ferroptosis? PLoS Biol. 2018;16(5):e2006203. doi: 10.1371/journal.pbio.2006203 29795546

27. Sykiotis GP, Bohmann D. Keap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila. Dev Cell. 2008;14(1):76–85. doi: 10.1016/j.devcel.2007.12.002 18194654

28. Pinal N, Martín M, Medina I, Morata G. Short-term activation of the Jun N-terminal kinase pathway in apoptosis-deficient cells of Drosophila induces tumorigenesis. Nat Commun. 2018;9(1):1541. doi: 10.1038/s41467-018-04000-6 29670104

29. Santabárbara-Ruiz P, López-Santillán M, Martínez-Rodríguez I, Binagui-Casas A, Pérez L, Milán M, et al. ROS-Induced JNK and p38 Signaling Is Required for Unpaired Cytokine Activation during Drosophila Regeneration. PLoS Genet. 2015;11(10):e1005595. doi: 10.1371/journal.pgen.1005595 26496642

30. Ferreira C, Bucchini D, Martin ME, Levi S, Arosio P, Grandchamp B, et al. Early embryonic lethality of H ferritin gene deletion in mice. J Biol Chem. 2000;275(5):3021–4. doi: 10.1074/jbc.275.5.3021 10652280

31. Li W, Garringer HJ, Goodwin CB, Richine B, Acton A, VanDuyn N, et al. Systemic and cerebral iron homeostasis in ferritin knock-out mice. PLoS One. 2015;10(1):e0117435. doi: 10.1371/journal.pone.0117435 25629408

32. Xiao G, Liu ZH, Zhao M, Wang HL, Zhou B. Transferrin 1 Functions in Iron Trafficking and Genetically Interacts with Ferritin in Drosophila melanogaster. Cell Rep. 2019;26(3):748–58.e5. doi: 10.1016/j.celrep.2018.12.053 30650364

33. Yoon S, Cho B, Shin M, Koranteng F, Cha N, Shim J. Iron Homeostasis Controls Myeloid Blood Cell Differentiation in Drosophila. Mol Cells. 2017;40(12):976–85. doi: 10.14348/molcells.2017.0287 29237257

34. Mandilaras K, Missirlis F. Genes for iron metabolism influence circadian rhythms in Drosophila melanogaster. Metallomics. 2012;4(9):928–36. doi: 10.1039/c2mt20065a 22885802

35. Levayer R, Moreno E. Mechanisms of cell competition: themes and variations. J Cell Biol. 2013;200(6):689–98. doi: 10.1083/jcb.201301051 23509066

36. de la Cova C. Myc in model organisms: A view from the fly room. seminars in cancer biology. 2006;16:303–12. doi: 10.1016/j.semcancer.2006.07.010 16916612

37. Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, Apple F, et al. Ferritin: a cytoprotective antioxidant strategem of endothelium. J Biol Chem. 1992;267(25):18148–53. 1517245

38. Lin F, Girotti AW. Hemin-enhanced resistance of human leukemia cells to oxidative killing: antisense determination of ferritin involvement. Arch Biochem Biophys. 1998;352(1):51–8. doi: 10.1006/abbi.1998.0588 9521813

39. Darshan D, Vanoaica L, Richman L, Beermann F, Kühn LC. Conditional deletion of ferritin H in mice induces loss of iron storage and liver damage. Hepatology. 2009;50(3):852–60. doi: 10.1002/hep.23058 19492434

40. Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, Alvarez K, et al. Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species. Cell. 2004;119(4):529–42. doi: 10.1016/j.cell.2004.10.017 15537542

41. Yu H, Guo P, Xie X, Wang Y, Chen G. Ferroptosis, a new form of cell death, and its relationships with tumourous diseases. J Cell Mol Med. 2017;21(4):648–57. doi: 10.1111/jcmm.13008 27860262

42. Wu J, Minikes AM, Gao M, Bian H, Li Y, Stockwell BR, et al. Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling. Nature. 2019;572(7769):402–6. doi: 10.1038/s41586-019-1426-6 31341276

43. Kolotuev I. Positional correlative anatomy of invertebrate model organisms increases efficiency of TEM data production. Microsc Microanal. 2014;20(5):1392–403. doi: 10.1017/S1431927614012999 25180638

44. Kolotuev I, Schwab Y, Labouesse M. A precise and rapid mapping protocol for correlative light and electron microscopy of small invertebrate organisms. Biol Cell. 2009;102(2):121–32. doi: 10.1042/BC20090096 19807690

45. Daniel E, Daudé M, Kolotuev I, Charish K, Auld V, Le Borgne R. Coordination of Septate Junctions Assembly and Completion of Cytokinesis in Proliferative Epithelial Tissues. Curr Biol. 2018;28(9):1380–91.e4. doi: 10.1016/j.cub.2018.03.034 29706514