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A simultaneous release of SOD1 with cytochrome c regulates mitochondria-dependent apoptosis

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Abstract

To elucidate the significance of mitochondrial localization of Cu/Zn-SOD (SOD1), we studied the relationship between the release of mitochondrial SOD1 and apoptosis. Kinetic analysis using HL-60 cells showed that both mitochondria-dependent and mitochondria-independent pro-apoptotic drugs, such as staurosporine and actinomycin D, increased the generation of reactive oxygen species (ROS) and decreased mitochondrial membrane potential (Δψ). ROS generation by these drugs was inhibited by Mn (III) tetrakis (5,10,15,20-benzoic acid) porphyrin (MnTBAP), a cell membrane-permeable SOD mimetic. However, MnTBAP inhibited the apoptosis induced by staurosporine but not by actinomycin D. MnTBAP failed to inhibit Δψ decrease and release of SOD1 and cytochrome c induced by actinomycin D. Moreover, 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS), an inhibitor of voltage-dependent anion channel (VDAC), inhibited the release of the two proteins and apoptosis induced by staurosporine but not actinomycin D. These results suggest that ROS plays an important role in mitochondria-dependent but not mitochondria-independent apoptosis and that the release of SOD1 increases the susceptibility of mitochondria to oxidative stress, thereby enhancing a vicious cycle leading to apoptosis.

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Acknowledgments

This work was supported by Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology (16590252 and 14370062), and 21st Century COE Program “Base to Overcome Fatigue” supported by MEXT, Japan. This work was also supported by the Sasakawa Scientific Research Grant from The Japan Science Society. The authors thank Prof. S. Tsuyoshi Ohnishi for his critical reading of the manuscript.

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  1. Department of Biochemistry and Molecular Pathology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno, Osaka, 545-8585, Japan

    Quan Li, Eisuke F. Sato, Xiaoping Zhu & Masayasu Inoue

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  1. Quan Li
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  2. Eisuke F. Sato
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  3. Xiaoping Zhu
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  4. Masayasu Inoue
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Correspondence to Eisuke F. Sato.

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Li, Q., Sato, E.F., Zhu, X. et al. A simultaneous release of SOD1 with cytochrome c regulates mitochondria-dependent apoptosis. Mol Cell Biochem 322, 151–159 (2009). https://doi.org/10.1007/s11010-008-9952-9

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  • DOI: https://doi.org/10.1007/s11010-008-9952-9

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