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Mitochondrial translocation of cofilin is an early step in apoptosis induction

Nature Cell Biology volume 5, pages 1083–1089 (2003)Cite this article

Abstract

Increasing evidence suggests that movement of key proteins in or out of mitochondria during apoptosis is essential for the regulation of apoptosis. Here, we report identification of the actin-binding protein cofilin by a proteomic approach, as such a factor translocated from cytosol into mitochondria after induction of apoptosis. We found that after induction of apoptosis, cofilin was translocated to mitochondria before release of cytochrome c. Reduction of cofilin protein levels with small-interfering RNA (siRNA) resulted in inhibition of both cytochrome c release and apoptosis. Only dephosphorylated cofilin was translocated to mitochondria, and the cofilin S3D mutant, which mimicks the phosphorylated form, suppressed mitochondrial translocation and apoptosis. Translocation was achieved through exposure of an amino-terminal mitochondrial targeting signal in combination with carboxy-terminal sequences. When correctly targeted to mitochondria, cofilin induced massive apoptosis. The apoptosis-inducing ability of cofilin, but not its mitochondrial localization, was dependent on the functional actin-binding domain. Thus, domains involved in mitochondrial targeting and actin binding are indispensable for its pro-apoptotic function. Our data suggest that cofilin has an important function during the initiation phase of apoptosis.

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Figure 1: Translocation of cofilin at an early stage of apoptosis.
Figure 2: Silencing of cofilin expression blocks cytochrome c release and inhibits apoptosis.
Figure 3: Phosphorlylation status of cofilin.
Figure 4: Mitochondria-localized cofilin induces apoptosis.
Figure 5: The actin-binding domain of cofilin is required for pro-apoptotic activity.

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Acknowledgements

We are grateful to Y. Samstag (Institute for Immunology, Heidelberg, Germany) and H. Abe (Chiba University, Chiba, Japan) for anti-cofilin antibodies. We are also grateful to B. Luen Tang, E. Manser, A. Porter, S.-L. Chan and N. Fu for critical comments and valuable discussion about the manuscript. This work was supported by Agency for Science, Technology and Research (A*STAR) in Singapore.

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Authors and Affiliations

  1. Laboratories of Apoptosis Regulation, National Institute of Singapore, 30 Medical Drive, Singapore, 117609

    Boon Tin Chua, Christiane Volbracht & Peng Li

  2. Mechanisms of Apoptosis in Mammalian Cells, National Institute of Singapore, 30 Medical Drive, Singapore, 117609

    Kuan Onn Tan & Victor C. Yu

  3. Proteomics, Institute of Molecular and Cell Biology, National Institute of Singapore, 30 Medical Drive, Singapore, 117609

    Rong Li

  4. Adjunct staff of the Department of Pharmacology, National University of Singapore, 18 Medical Drive, Singapore, 119260

    Victor C. Yu

  5. Department of Biology, Hong Kong University of Science and Technology, Clear water bay, Kowloon, Hong Kong

    Peng Li

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  1. Boon Tin Chua
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Correspondence to Peng Li.

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Chua, B., Volbracht, C., Tan, K. et al. Mitochondrial translocation of cofilin is an early step in apoptosis induction. Nat Cell Biol 5, 1083–1089 (2003). https://doi.org/10.1038/ncb1070

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