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Mitochondrial aggregation precedes cytochrome c release from mitochondria during apoptosis

Oncogene volume 22, pages 5579–5585 (2003)Cite this article

Abstract

Mitochondria play a central role in apoptotic signaling pathways. Upon exposure to apoptotic stimuli, mitochondria release cytochrome c to the cytoplasm and activate caspase cascade leading to cell death. However, the events upstream of cytochrome c release are not fully understood. Here, we quantitate mitochondrial aggregation in situ using a novel laser scanning cytometry technique and reveal that mitochondria aggregate during apoptosis in a budding-like shape. The quantitative analysis reveals that mitochondrial aggregation is not inhibited by caspase-3 inhibitor ZEVD. Furthermore, bcl-xL transfection cannot suppress mitochondrial aggregation. However, overexpression of bcl-xL inhibits cytochrome c release from mitochondria. Therefore, mitochondrial aggregation is an event upstream of cytochrome c release during apoptosis. This mitochondrial aggregation was not observed in human leukemia H9 cells where apoptosis occurs in a mitochondria-independent fashion. Our studies imply that changes in the localization of mitochondria participate in the regulation of apoptosis through cytochrome c release.

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Acknowledgements

We thank Drs Hiroyuki Seimiya, Tetsuo Mashima, Mikihiko Naito, Akihiro Tomida, Shin-ichi Torii, Hitoshi Nakamura, and Robert H. Shoemaker for helpful discussions and critical review of the manuscript, Ms Chizuko Hashimoto, Atsuko Yamashita for technical assistance. We also thank Kazuhiko Nakayama and Hitoshi Miyagi (Olympus, Japan) for help with the LSC experiments. This study was supported by a special grant for Advanced Research on Cancer, a Grant-in-Aid for Cancer Research from the Ministry of Education, Science, Sports and Culture, Japan.

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Authors and Affiliations

  1. Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, 113-0032, Japan

    Naomi Haga, Naoya Fujita & Takashi Tsuruo

  2. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 170-8455, Japan

    Takashi Tsuruo

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  1. Naomi Haga
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  2. Naoya Fujita
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Haga, N., Fujita, N. & Tsuruo, T. Mitochondrial aggregation precedes cytochrome c release from mitochondria during apoptosis. Oncogene 22, 5579–5585 (2003). https://doi.org/10.1038/sj.onc.1206576

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