Letter abstract
Nature Cell Biology 11, 958 - 966 (2009)
Published online: 5 July 2009 | doi:10.1038/ncb1907
Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice
Naotada Ishihara1,9, Masatoshi Nomura2,9, Akihiro Jofuku3,9, Hiroki Kato3, Satoshi O. Suzuki4, Keiji Masuda5, Hidenori Otera3, Yae Nakanishi2, Ikuya Nonaka6, Yu-ichi Goto6, Naoko Taguchi7, Hidetaka Morinaga2, Maki Maeda1, Ryoichi Takayanagi2, Sadaki Yokota8 & Katsuyoshi Mihara3
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.
- Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka 812-8582, Japan.
- Department of Molecular Biology, Kyushu University, Fukuoka 812-8582, Japan.
- Department of Neuropathology, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan.
- Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan.
- Department of Mental Retardation and Birth Development Research, National Institute of Neuroscience, Kodaira 187-8502, Japan.
- Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
- Pharmaceutical Sciences, Nagasaki International University, Sasebo 859-3298, Japan.
- These authors contributed equally to this paper.
Correspondence to: Katsuyoshi Mihara3 e-mail: mihara@cell.med.kyushu-u.ac.jp
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