Drosophila Caliban preserves intestinal homeostasis and lifespan through regulating mitochondrial dynamics and redox state in enterocytes

Autoři: Zhaoxia Dai aff001;  Dong Li aff001;  Xiao Du aff001;  Ying Ge aff001;  Deborah A. Hursh aff003;  Xiaolin Bi aff002
Působiště autorů: The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China aff001;  School of Medicine, Nantong University, Nantong, China aff002;  Division of Cellular and Gene Therapies, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, United States of America aff003;  College of Basic Medical Sciences, Dalian Medical University, Dalian, China aff004
Vyšlo v časopise: Drosophila Caliban preserves intestinal homeostasis and lifespan through regulating mitochondrial dynamics and redox state in enterocytes. PLoS Genet 16(10): e32767. doi:10.1371/journal.pgen.1009140
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009140


Precise regulation of stem cell activity is crucial for tissue homeostasis. In Drosophila, intestinal stem cells (ISCs) maintain the midgut epithelium and respond to oxidative challenges. However, the connection between intestinal homeostasis and redox signaling remains obscure. Here we find that Caliban (Clbn) functions as a regulator of mitochondrial dynamics in enterocytes (ECs) and is required for intestinal homeostasis. The clbn knock-out flies have a shortened lifespan and lose the intestinal homeostasis. Clbn is highly expressed and localizes to the outer membrane of mitochondria in ECs. Mechanically, Clbn mediates mitochondrial dynamics in ECs and removal of clbn leads to mitochondrial fragmentation, accumulation of reactive oxygen species, ECs damage, activation of JNK and JAK-STAT signaling pathways. Moreover, multiple mitochondria-related genes are differentially expressed between wild-type and clbn mutated flies by a whole-genome transcriptional profiling. Furthermore, loss of clbn promotes tumor growth in gut generated by activated Ras in intestinal progenitor cells. Our findings reveal an EC-specific function of Clbn in regulating mitochondrial dynamics, and provide new insight into the functional link among mitochondrial redox modulation, tissue homeostasis and longevity.

Klíčová slova:

Cell differentiation – Cloning – DAPI staining – Drosophila melanogaster – Gastrointestinal tract – Homeostasis – Mitochondria – Stem cells


1. Li H, Jasper H. Gastrointestinal stem cells in health and disease: from flies to humans. Disease models & mechanisms. 2016;9(5):487–99.

2. Jiang H, Edgar BA. Intestinal stem cells in the adult Drosophila midgut. Experimental cell research. 2011;317(19):2780–8. doi: 10.1016/j.yexcr.2011.07.020 21856297

3. Micchelli CA. The origin of intestinal stem cells in Drosophila. Developmental dynamics: an official publication of the American Association of Anatomists. 2012;241(1):85–91.

4. Micchelli CA, Perrimon N. Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature. 2006;439(7075):475–9. doi: 10.1038/nature04371 16340959

5. Ohlstein B, Spradling A. The adult Drosophila posterior midgut is maintained by pluripotent stem cells. Nature. 2006;439(7075):470–4. doi: 10.1038/nature04333 16340960

6. Guo Z, Ohlstein B. Stem cell regulation. Bidirectional Notch signaling regulates Drosophila intestinal stem cell multipotency. Science. 2015;350(6263).

7. Biteau B, Jasper H. Slit/Robo signaling regulates cell fate decisions in the intestinal stem cell lineage of Drosophila. Cell reports. 2014;7(6):1867–75. doi: 10.1016/j.celrep.2014.05.024 24931602

8. Ohlstein B, Spradling A. Multipotent Drosophila intestinal stem cells specify daughter cell fates by differential notch signaling. Science. 2007;315(5814):988–92. doi: 10.1126/science.1136606 17303754

9. Perdigoto CN, Schweisguth F, Bardin AJ. Distinct levels of Notch activity for commitment and terminal differentiation of stem cells in the adult fly intestine. Development. 2011;138(21):4585–95. doi: 10.1242/dev.065292 21965616

10. Zeng X, Hou SX. Enteroendocrine cells are generated from stem cells through a distinct progenitor in the adult Drosophila posterior midgut. Development. 2015;142(4):644–53. doi: 10.1242/dev.113357 25670791

11. Bardin AJ, Perdigoto CN, Southall TD, Brand AH, Schweisguth F. Transcriptional control of stem cell maintenance in the Drosophila intestine. Development. 2010;137(5):705–14. doi: 10.1242/dev.039404 20147375

12. Biteau B, Hochmuth CE, Jasper H. JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. Cell stem cell. 2008;3(4):442–55. doi: 10.1016/j.stem.2008.07.024 18940735

13. Buchon N, Broderick NA, Kuraishi T, Lemaitre B. Drosophila EGFR pathway coordinates stem cell proliferation and gut remodeling following infection. BMC biology. 2010;8:152. doi: 10.1186/1741-7007-8-152 21176204

14. Lin G, Xu N, Xi R. Paracrine Wingless signalling controls self-renewal of Drosophila intestinal stem cells. Nature. 2008;455(7216):1119–23. doi: 10.1038/nature07329 18806781

15. Jiang H, Patel PH, Kohlmaier A, Grenley MO, McEwen DG, Edgar BA. Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut. Cell. 2009;137(7):1343–55. doi: 10.1016/j.cell.2009.05.014 19563763

16. Tian A, Jiang J. Intestinal epithelium-derived BMP controls stem cell self-renewal in Drosophila adult midgut. eLife. 2014;3:e01857. doi: 10.7554/eLife.01857 24618900

17. Ren F, Wang B, Yue T, Yun EY, Ip YT, Jiang J. Hippo signaling regulates Drosophila intestine stem cell proliferation through multiple pathways. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(49):21064–9. doi: 10.1073/pnas.1012759107 21078993

18. Tan DQ, Suda T. Reactive Oxygen Species and Mitochondrial Homeostasis as Regulators of Stem Cell Fate and Function. Antioxidants & redox signaling. 2018;29(2):149–68.

19. Khacho M, Slack RS. Mitochondrial and Reactive Oxygen Species Signaling Coordinate Stem Cell Fate Decisions and Life Long Maintenance. Antioxidants & redox signaling. 2018;28(11):1090–101.

20. Moro L. Mitochondrial Dysfunction in Aging and Cancer. J Clin Med. 2019;8(11).

21. Owusu-Ansah E, Banerjee U. Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature. 2009;461(7263):537–41. doi: 10.1038/nature08313 19727075

22. Noble M, Smith J, Power J, Mayer-Proschel M. Redox state as a central modulator of precursor cell function. Annals of the New York Academy of Sciences. 2003;991:251–71. doi: 10.1111/j.1749-6632.2003.tb07481.x 12846992

23. Khacho M, Clark A, Svoboda DS, Azzi J, MacLaurin JG, Meghaizel C, et al. Mitochondrial Dynamics Impacts Stem Cell Identity and Fate Decisions by Regulating a Nuclear Transcriptional Program. Cell stem cell. 2016;19(2):232–47. doi: 10.1016/j.stem.2016.04.015 27237737

24. Kasahara A, Cipolat S, Chen Y, Dorn GW, 2nd, Scorrano L. Mitochondrial fusion directs cardiomyocyte differentiation via calcineurin and Notch signaling. Science. 2013;342(6159):734–7. doi: 10.1126/science.1241359 24091702

25. Luchsinger LL, de Almeida MJ, Corrigan DJ, Mumau M, Snoeck HW. Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential. Nature. 2016;529(7587):528–31. doi: 10.1038/nature16500 26789249

26. Jiang JC, Stumpferl SW, Jazwinski SM. Dual roles of mitochondrial fusion gene FZO1 in yeast age asymmetry and in longevity mediated by a novel ATG32-dependent retrograde response. Biogerontology. 2019;20(1):93–107. doi: 10.1007/s10522-018-9779-z 30298458

27. Jones RM, Luo L, Ardita CS, Richardson AN, Kwon YM, Mercante JW, et al. Symbiotic lactobacilli stimulate gut epithelial proliferation via Nox-mediated generation of reactive oxygen species. The EMBO journal. 2013;32(23):3017–28. doi: 10.1038/emboj.2013.224 24141879

28. Buchon N, Broderick NA, Chakrabarti S, Lemaitre B. Invasive and indigenous microbiota impact intestinal stem cell activity through multiple pathways in Drosophila. Genes & development. 2009;23(19):2333–44.

29. Wang L, Zeng X, Ryoo HD, Jasper H. Integration of UPRER and oxidative stress signaling in the control of intestinal stem cell proliferation. PLoS genetics. 2014;10(8):e1004568. doi: 10.1371/journal.pgen.1004568 25166757

30. Hochmuth CE, Biteau B, Bohmann D, Jasper H. Redox regulation by Keap1 and Nrf2 controls intestinal stem cell proliferation in Drosophila. Cell stem cell. 2011;8(2):188–99. doi: 10.1016/j.stem.2010.12.006 21295275

31. Deng H, Takashima S, Paul M, Guo M, Hartenstein V. Mitochondrial dynamics regulates Drosophila intestinal stem cell differentiation. Cell death discovery. 2018;4:17.

32. Bi X, Jones T, Abbasi F, Lee H, Stultz B, Hursh DA, et al. Drosophila caliban, a nuclear export mediator, can function as a tumor suppressor in human lung cancer cells. Oncogene. 2005;24(56):8229–39. doi: 10.1038/sj.onc.1208962 16103875

33. Wang Y, Wang Z, Joshi BH, Puri RK, Stultz B, Yuan Q, et al. The tumor suppressor Caliban regulates DNA damage-induced apoptosis through p53-dependent and -independent activity. Oncogene. 2013;32(33):3857–66. doi: 10.1038/onc.2012.395 22964637

34. Song F, Li D, Wang Y, Bi X. Drosophila Caliban mediates G1-S transition and ionizing radiation induced S phase checkpoint. Cell cycle. 2018;17(18):2256–67. doi: 10.1080/15384101.2018.1524237 30231800

35. Wu Z, Tantray I, Lim J, Chen S, Li Y, Davis Z, et al. MISTERMINATE Mechanistically Links Mitochondrial Dysfunction with Proteostasis Failure. Molecular cell. 2019;75(4):835–48 e8. doi: 10.1016/j.molcel.2019.06.031 31378462

36. Jiang H, Tian A, Jiang J. Intestinal stem cell response to injury: lessons from Drosophila. Cellular and molecular life sciences: CMLS. 2016;73(17):3337–49. doi: 10.1007/s00018-016-2235-9 27137186

37. Westermann B. Mitochondrial dynamics in model organisms: what yeasts, worms and flies have taught us about fusion and fission of mitochondria. Semin Cell Dev Biol. 2010;21(6):542–9. doi: 10.1016/j.semcdb.2009.12.003 20006727

38. Sheridan C, Martin SJ. Mitochondrial fission/fusion dynamics and apoptosis. Mitochondrion. 2010;10(6):640–8. doi: 10.1016/j.mito.2010.08.005 20727425

39. Shen PS, Park J, Qin Y, Li X, Parsawar K, Larson MH, et al. Protein synthesis. Rqc2p and 60S ribosomal subunits mediate mRNA-independent elongation of nascent chains. Science. 2015;347(6217):75–8. doi: 10.1126/science.1259724 25554787

40. Joazeiro CAP. Ribosomal Stalling During Translation: Providing Substrates for Ribosome-Associated Protein Quality Control. Annual review of cell and developmental biology. 2017;33:343–68. doi: 10.1146/annurev-cellbio-111315-125249 28715909

41. Gaudet P, Livstone MS, Lewis SE, Thomas PD. Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics. 2011;12(5):449–62. doi: 10.1093/bib/bbr042 21873635

42. Horiuchi D, Barkus RV, Pilling AD, Gassman A, Saxton WM. APLIP1, a kinesin binding JIP-1/JNK scaffold protein, influences the axonal transport of both vesicles and mitochondria in Drosophila. Current biology: CB. 2005;15(23):2137–41. doi: 10.1016/j.cub.2005.10.047 16332540

43. Webel R, Haug-Collet K, Pearson B, Szerencsei RT, Winkfein RJ, Schnetkamp PP, et al. Potassium-dependent sodium-calcium exchange through the eye of the fly. Annals of the New York Academy of Sciences. 2002;976:300–14. doi: 10.1111/j.1749-6632.2002.tb04753.x 12502573

44. Marelja Z, Dambowsky M, Bolis M, Georgiou ML, Garattini E, Missirlis F, et al. The four aldehyde oxidases of Drosophila melanogaster have different gene expression patterns and enzyme substrate specificities. The Journal of experimental biology. 2014;217(Pt 12):2201–11. doi: 10.1242/jeb.102129 24737760

45. Saisawang C, Wongsantichon J, Ketterman AJ. A preliminary characterization of the cytosolic glutathione transferase proteome from Drosophila melanogaster. The Biochemical journal. 2012;442(1):181–90. doi: 10.1042/BJ20111747 22082028

46. Li H, Qi Y, Jasper H. Dpp signaling determines regional stem cell identity in the regenerating adult Drosophila gastrointestinal tract. Cell reports. 2013;4(1):10–8. doi: 10.1016/j.celrep.2013.05.040 23810561

47. Li Z, Zhang Y, Han L, Shi L, Lin X. Trachea-derived dpp controls adult midgut homeostasis in Drosophila. Developmental cell. 2013;24(2):133–43. doi: 10.1016/j.devcel.2012.12.010 23369712

48. Biteau B, Karpac J, Supoyo S, Degennaro M, Lehmann R, Jasper H. Lifespan extension by preserving proliferative homeostasis in Drosophila. PLoS genetics. 2010;6(10):e1001159. doi: 10.1371/journal.pgen.1001159 20976250

49. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. doi: 10.1016/j.cell.2011.02.013 21376230

50. Biteau B, Jasper H. EGF signaling regulates the proliferation of intestinal stem cells in Drosophila. Development. 2011;138(6):1045–55. doi: 10.1242/dev.056671 21307097

51. Patel PH, Dutta D, Edgar BA. Niche appropriation by Drosophila intestinal stem cell tumours. Nature cell biology. 2015;17(9):1182–92. doi: 10.1038/ncb3214 26237646

52. West AP, Shadel GS, Ghosh S. Mitochondria in innate immune responses. Nature reviews Immunology. 2011;11(6):389–402. doi: 10.1038/nri2975 21597473

53. Manent J, Banerjee S, de Matos Simoes R, Zoranovic T, Mitsiades C, Penninger JM, et al. Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species. Oncogene. 2017;36(40):5658–60. doi: 10.1038/onc.2017.239 28980625

54. Zhang Y, Chen Y, Gucek M, Xu H. The mitochondrial outer membrane protein MDI promotes local protein synthesis and mtDNA replication. The EMBO journal. 2016;35(10):1045–57. doi: 10.15252/embj.201592994 27053724

55. Dutta D, Xiang J, Edgar BA. RNA expression profiling from FACS-isolated cells of the Drosophila intestine. Curr Protoc Stem Cell Biol. 2013;27:Unit 2F

56. Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. Omics: a journal of integrative biology. 2012;16(5):284–7. doi: 10.1089/omi.2011.0118 22455463

57. Rera M, Azizi MJ, Walker DW. Organ-specific mediation of lifespan extension: more than a gut feeling? Ageing research reviews. 2013;12(1):436–44. doi: 10.1016/j.arr.2012.05.003 22706186

58. Ryu JH, Kim SH, Lee HY, Bai JY, Nam YD, Bae JW, et al. Innate immune homeostasis by the homeobox gene caudal and commensal-gut mutualism in Drosophila. Science. 2008;319(5864):777–82. doi: 10.1126/science.1149357 18218863

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