Letter | Published:

Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice

Nature Cell Biology volume 11, pages 958966 (2009) | Download Citation

Abstract

Mitochondrial morphology is dynamically controlled by a balance between fusion and fission. The physiological importance of mitochondrial fission in vertebrates is less clearly defined than that of mitochondrial fusion. Here we show that mice lacking the mitochondrial fission GTPase Drp1 have developmental abnormalities, particularly in the forebrain, and die after embryonic day 12.5. Neural cell-specific (NS) Drp1−/− mice die shortly after birth as a result of brain hypoplasia with apoptosis. Primary culture of NS-Drp1−/− mouse forebrain showed a decreased number of neurites and defective synapse formation, thought to be due to aggregated mitochondria that failed to distribute properly within the cell processes. These defects were reflected by abnormal forebrain development and highlight the importance of Drp1-dependent mitochondrial fission within highly polarized cells such as neurons. Moreover, Drp1−/− murine embryonic fibroblasts and embryonic stem cells revealed that Drp1 is required for a normal rate of cytochrome c release and caspase activation during apoptosis, although mitochondrial outer membrane permeabilization, as examined by the release of Smac/Diablo and Tim8a, may occur independently of Drp1 activity.

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Acknowledgements

We thank Dr Toshihiko Oka, Dr Noboru Mizushima, Dr Akira Kondo and members of the Mihara laboratory for productive discussions. We also thank Dr Richard Youle and Dr Atsushi Tanaka for critical reading of the manuscript and for advice. This work was supported by grants from the Ministry of Education, Science, and Culture of Japan, from the Human Frontier Science Program, from Core Research from Evolutional Science and Technology, and from the Takeda Science Foundation.

Author information

Author notes

    • Naotada Ishihara
    • , Masatoshi Nomura
    •  & Akihiro Jofuku

    These authors contributed equally to this paper.

Affiliations

  1. Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.

    • Naotada Ishihara
    •  & Maki Maeda
  2. Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka 812-8582, Japan.

    • Masatoshi Nomura
    • , Yae Nakanishi
    • , Hidetaka Morinaga
    •  & Ryoichi Takayanagi
  3. Department of Molecular Biology, Kyushu University, Fukuoka 812-8582, Japan.

    • Akihiro Jofuku
    • , Hiroki Kato
    • , Hidenori Otera
    •  & Katsuyoshi Mihara
  4. Department of Neuropathology, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan.

    • Satoshi O. Suzuki
  5. Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan.

    • Keiji Masuda
  6. Department of Mental Retardation and Birth Development Research, National Institute of Neuroscience, Kodaira 187-8502, Japan.

    • Ikuya Nonaka
    •  & Yu-ichi Goto
  7. Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.

    • Naoko Taguchi
  8. Pharmaceutical Sciences, Nagasaki International University, Sasebo 859-3298, Japan.

    • Sadaki Yokota

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Contributions

M.N., A.J., K. Masuda, N.I., Y.N. and H.M. contributed to the generation of Drp1−/− mice and NS-Drp1−/− mice, and S.O.S., A.J. and H.K. analysed the phenotypes mainly in the brain. S.O.S. performed the diagnoses on the mice brain. S.O.S., A.J., N.I. and H.K. contributed to analyses of neuronal primary cultured cells of NS-Drp1−/− mice. N.I., A.J., N.T. and M.M. contributed to analyses of Drp1−/− ES and MEF cells, and H.O. and A.J. analysed the apoptotic response. I.N. and Y.G. contributed to histochemical EM for Drp1−/− mice brain, and Y.S. contributed to all conventional EM analyses. K. Mihara planned the project, analysed the data, and wrote the manuscript except the part relating to medical diagnosis for the brains of Drp1-knockout mice, which was written by S.O.S.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Katsuyoshi Mihara.

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DOI

https://doi.org/10.1038/ncb1907

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