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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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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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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DOI: https://doi.org/10.1038/nature03316
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