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DRP-1-mediated mitochondrial fragmentation during EGL-1-induced cell death in C. elegans

Nature volume 433, pages 754–760 (2005)Cite this article

Abstract

Genetic analyses in Caenorhabditis elegans have been instrumental in the elucidation of the central cell-death machinery, which is conserved from C. elegans to mammals1,2. One possible difference that has emerged is the role of mitochondria. By releasing cytochrome c, mitochondria are involved in the activation of caspases in mammals3,4. However, there has previously been no evidence that mitochondria are involved in caspase activation in C. elegans. Here we show that mitochondria fragment in cells that normally undergo programmed cell death during C. elegans development. Mitochondrial fragmentation is induced by the BH3-only protein EGL-1 and can be blocked by mutations in the bcl-2-like gene ced-9, indicating that members of the Bcl-2 family might function in the regulation of mitochondrial fragmentation in apoptotic cells. Mitochondrial fragmentation is independent of CED-4/Apaf-1 and CED-3/caspase, indicating that it occurs before or simultaneously with their activation. Furthermore, DRP-1/dynamin-related protein, a key component of the mitochondrial fission machinery, is required and sufficient to induce mitochondrial fragmentation and programmed cell death during C. elegans development. These results assign an important role to mitochondria in the cell-death pathway in C. elegans.

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Figure 1: Mitochondrial morphology in cells undergoing programmed cell death in C. elegans.
Figure 2: Expression of drp-1(K40A) or drp-1(wt).
Figure 3: ced-9(n2812lf) blocks the ability of EGL-1 and DRP-1 to induce mitochondrial fragmentation.
Figure 4: Genetic and molecular model of the activation of programmed cell death in C. elegans.

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References

  1. Horvitz, H. R. Genetic control of programmed cell death in the nematode Caenorhabditis elegans . Cancer Res. 59, 1701s–1706s (1999)

    CAS  PubMed  Google Scholar 

  2. Danial, N. N. & Korsmeyer, S. J. Cell death: critical control points. Cell 116, 205–219 (2004)

    Article  CAS  Google Scholar 

  3. Newmeyer, D. D. & Ferguson-Miller, S. Mitochondria: releasing power for life and unleashing the machineries of death. Cell 112, 481–490 (2003)

    Article  CAS  Google Scholar 

  4. Jiang, X. & Wang, X. Cytochrome C-mediated apoptosis. Annu. Rev. Biochem. 73, 87–106 (2004)

    Article  CAS  Google Scholar 

  5. Sulston, J. E. & Horvitz, H. R. Post-embryonic cell lineages of the nematode, Caenorhabditis elegans . Dev. Biol. 56, 110–156 (1977)

    Article  CAS  Google Scholar 

  6. Sulston, J. E., Schierenberg, E., White, J. G. & Thomson, J. N. The embryonic cell lineage of the nematode Caenorhabditis elegans . Dev. Biol. 100, 64–119 (1983)

    Article  CAS  Google Scholar 

  7. Chen, F. et al. Translocation of C. elegans CED-4 to nuclear membranes during programmed cell death. Science 287, 1485–1489 (2000)

    Article  ADS  CAS  Google Scholar 

  8. Conradt, B. & Horvitz, H. R. The TRA-1A sex determination protein of C. elegans regulates sexually dimorphic cell deaths by repressing the egl-1 cell death activator gene. Cell 98, 317–327 (1999)

    Article  CAS  Google Scholar 

  9. Bossy-Wetzel, E., Barsoum, M. J., Godzik, A., Schwarzenbacher, R. & Lipton, S. A. Mitochondrial fission in apoptosis, neurodegeneration and aging. Curr. Opin. Cell Biol. 15, 706–716 (2003)

    Article  CAS  Google Scholar 

  10. Karbowski, M. & Youle, R. J. Dynamics of mitochondrial morphology in healthy cells and during apoptosis. Cell Death Differ. 10, 870–880 (2003)

    Article  CAS  Google Scholar 

  11. Frank, S. et al. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev. Cell 1, 515–525 (2001)

    Article  CAS  Google Scholar 

  12. Breckenridge, D. G., Stojanovic, M., Marcellus, R. C. & Shore, G. C. Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol. J. Cell Biol. 160, 1115–1127 (2003)

    Article  CAS  Google Scholar 

  13. Conradt, B. & Horvitz, H. R. The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9. Cell 93, 519–529 (1998)

    Article  CAS  Google Scholar 

  14. Bloss, T. A., Witze, E. S. & Rothman, J. H. Suppression of CED-3-independent apoptosis by mitochondrial βNAC in Caenorhabditis elegans . Nature 424, 1066–1071 (2003)

    Article  ADS  CAS  Google Scholar 

  15. van der Bliek, A. M. Functional diversity in the dynamin family. Trends Cell Biol. 9, 96–102 (1999)

    Article  CAS  Google Scholar 

  16. Labrousse, A. M., Zappaterra, M. D., Rube, D. A. & van der Bliek, A. M. C. elegans dynamin-related protein DRP-1 controls severing of the mitochondrial outer membrane. Mol. Cell 4, 815–826 (1999)

    Article  CAS  Google Scholar 

  17. Shaw, J. M. & Nunnari, J. Mitochondrial dynamics and division in budding yeast. Trends Cell Biol. 12, 178–184 (2002)

    Article  CAS  Google Scholar 

  18. Reddien, P. W., Cameron, S. & Horvitz, H. R. Phagocytosis promotes programmed cell death in C. elegans . Nature 412, 198–202 (2001)

    Article  ADS  CAS  Google Scholar 

  19. Parrish, J., Metters, H., Chen, L. & Xue, D. Demonstration of the in vivo interaction of key cell death regulators by structure-based design of second-site suppressors. Proc. Natl Acad. Sci. USA 97, 11916–11921 (2000)

    Article  ADS  CAS  Google Scholar 

  20. Hengartner, M. O. & Horvitz, H. R. C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 76, 665–676 (1994)

    Article  CAS  Google Scholar 

  21. Hengartner, M. O., Ellis, R. E. & Horvitz, H. R. Caenorhabditis elegans gene ced-9 protects cells from programmed cell death. Nature 356, 494–499 (1992)

    Article  ADS  CAS  Google Scholar 

  22. Hengartner, M. O. & Horvitz, H. R. Activation of C. elegans cell death protein CED-9 by an amino-acid substitution in a domain conserved in Bcl-2. Nature 369, 318–320 (1994)

    Article  ADS  CAS  Google Scholar 

  23. Desagher, S. & Martinou, J. C. Mitochondria as the central control point of apoptosis. Trends Cell Biol. 10, 369–377 (2000)

    Article  CAS  Google Scholar 

  24. Karbowski, M. et al. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J. Cell Biol. 159, 931–938 (2002)

    Article  CAS  Google Scholar 

  25. Parrish, J. et al. Mitochondrial endonuclease G is important for apoptosis in C. elegans . Nature 412, 90–94 (2001)

    Article  ADS  CAS  Google Scholar 

  26. Wang, X., Yang, C., Chai, J., Shi, Y. & Xue, D. Mechanisms of AIF-mediated apoptotic DNA degradation in Caenorhabditis elegans . Science 298, 1587–1592 (2002)

    Article  ADS  CAS  Google Scholar 

  27. Riddle, D. L. & Albert, P. S. in C. elegans II (eds Riddle, D. L., Blumenthal, T., Meyer, B. J. & Priess, J. R.) 739–768 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1997)

    Google Scholar 

  28. Bloom, L. & Horvitz, H. R. The Caenorhabditis elegans gene unc-76 and its human homologs define a new gene family involved in axonal outgrowth and fasciculation. Proc. Natl Acad. Sci. USA 94, 3414–3419 (1997)

    Article  ADS  CAS  Google Scholar 

  29. Aspock, G., Ruvkun, G. & Burglin, T. R. The Caenorhabditis elegans ems class homeobox gene ceh-2 is required for M3 pharynx motoneuron function. Development 130, 3369–3378 (2003)

    Article  Google Scholar 

  30. Mello, C. & Fire, A. DNA transformation. Methods Cell Biol. 48, 451–482 (1995)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank E. Lambie, H. Hutter and members of the Conradt laboratory for comments on the manuscript; H. Schnabel and J. Hatzold for discussion; J. Hatzold for generating the integration bcIs51; A. van der Bliek for providing the plasmids myo-3::mitogfp, myo-3::drp-1 and myo-3::drp-1(K40A); S. Hell, S. Jakobs, G. Tavosanis, A. Vollmar and J. Chalcroft for their support with microscopy; and W. Neupert for his support throughout this study. This research was supported by funding from the Deutsche Forschungsgemeinschaft and the Friedrich-Baur-Stiftung to B.W. and by funding from the Max Planck Society, the European Molecular Biology Organization (EMBO Young Investigator Award) and the Howard Hughes Medical Institute (HHMI award to Dartmouth Medical School under the Biomedical Research Support Program for Medical Schools) to B.C.

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Authors and Affiliations

  1. Max Planck Institute of Neurobiology, Am Klopferspitz 18a, D-82152, Planegg-Martinsried, Germany

    Ravi Jagasia

  2. Institut für Physiologische Chemie, Universität München, D-81377, München, Germany

    Ravi Jagasia & Benedikt Westermann

  3. Department of Genetics, Dartmouth Medical School, 7400 Remsen, Hanover, New Hampshire, 03755, USA

    Ravi Jagasia, Phillip Grote & Barbara Conradt

  4. Zellbiologie, Universität Bayreuth, D-95440, Bayreuth, Germany

    Benedikt Westermann

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Correspondence to Barbara Conradt.

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Supplementary information

Supplementary Data

Includes Supplementary Tables S1-S4, figure legends for Supplementary Figures S1-S3, and Supplementary references. (DOC 95 kb)

Supplementary Figure 1

Mitochondrial morphology (rhodamine staining) in various cell-death defective mutants. (JPG 66 kb)

Supplementary Figure 2

DIC images of wild-type animals and various cell-death defective mutants treated with icd-1(RNAi). (JPG 60 kb)

Supplementary Figure 3

DIC images of wild-type animals, wild-type animals overexpressing drp-1(wt) or egl-1, and wild-type animals treated with icd-1(RNAi). (JPG 95 kb)

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Jagasia, R., Grote, P., Westermann, B. et al. DRP-1-mediated mitochondrial fragmentation during EGL-1-induced cell death in C. elegans. Nature 433, 754–760 (2005). https://doi.org/10.1038/nature03316

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