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A molecular mechanism for mimosine-induced apoptosis involving oxidative stress and mitochondrial activation

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Abstract

Mimosine, a non-protein amino acid, is mainly known for its action as a reversible inhibitor of DNA replication and, therefore, has been widely used as a cell cycle synchronizing agent. Recently, it has been shown that mimosine also induces apoptosis, as mainly reflected in its ability to elicit characteristic nuclear changes. The present study elucidates the mechanism underlying mimosine’s apoptotic effects, using the U-937 leukemia cell line. We now demonstrate that in isolated rat liver mitochondria, mimosine induces mitochondrial swelling that can be inhibited by cyclosporine A, indicative of permeability transition (PT) mega-channel opening. Mimosine-induced apoptosis was accompanied by formation of hydrogen peroxide and a decrease in reduced glutathione levels. The apoptotic process was partially inhibited by cyclosporine A and substantially blocked by the antioxidant N-acetylcysteine, suggesting an essential role for reactive oxygen species formation during the apoptotic processes. The apoptosis induced by mimosine was also accompanied by a decrease in mitochondrial membrane potential, cytochrome c release and caspase 3 and 9 activation. Our results thus imply that mimosine activates apoptosis through mitochondrial activation and formation of H2O2, both of which play functional roles in the induction of cell death.

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Acknowledgements

We thank Natalia Tsesin and Salah Abu-Hamad for help in preparing and isolating the rat liver mitochondria used in this study.

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Authors and Affiliations

  1. Institute of Hematology, Soroka University Medical Center, Beer Sheva, 84883, Israel

    Maher Hallak, Liat Vazana, Itai Levy & Ilana Nathan

  2. Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev , Beer Sheva, 84101, Israel

    Maher Hallak, Liat Vazana & Ilana Nathan

  3. Institute of Hematology, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel

    Ofer Shpilberg

  4. National Institute of Health, Bld.10 R10D09, Bethesda, MD, 20892-1855, USA

    Julia Mazar

Authors
  1. Maher Hallak
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  2. Liat Vazana
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  3. Ofer Shpilberg
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  4. Itai Levy
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  5. Julia Mazar
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  6. Ilana Nathan
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Correspondence to Ilana Nathan.

Additional information

Maher Hallak and Liat Vazana have contributed equally to the work.

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Hallak, M., Vazana, L., Shpilberg, O. et al. A molecular mechanism for mimosine-induced apoptosis involving oxidative stress and mitochondrial activation. Apoptosis 13, 147–155 (2008). https://doi.org/10.1007/s10495-007-0156-7

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  • DOI: https://doi.org/10.1007/s10495-007-0156-7

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