Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice
Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice
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DOI：
10.1038/ncb1907
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发表时间：
2009-08-01
影响因子：
21.3
通讯作者：
Mihara, Katsuyoshi
中科院分区：
文献类型：
--
作者：
Ishihara, Naotada;Nomura, Masatoshi;Mihara, Katsuyoshi
线粒体的形态是由融合和分裂之间的平衡动态控制的。在脊椎动物中，线粒体分裂的生理重要性不如线粒体融合的重要性明确。在这里，我们发现，缺乏线粒体分裂GTdR Drp 1的小鼠有发育异常，特别是在前脑，并在胚胎12.5天后死亡。神经细胞特异性（NS）Drp 1（-/-）小鼠出生后不久死亡，由于脑发育不全与细胞凋亡。NS-Drp 1（-/-）小鼠前脑的原代培养显示神经突数量减少和突触形成缺陷，认为这是由于聚集的线粒体未能在细胞过程中正确分布。这些缺陷反映在异常的前脑发育中，并突出了Drp 1依赖的线粒体分裂在高度极化的细胞（如神经元）中的重要性。此外，Drp 1（-/-）鼠胚胎成纤维细胞和胚胎干细胞显示，Drp 1是细胞色素c释放和caspase激活在细胞凋亡过程中的正常速率所需的，虽然线粒体外膜透化，检查释放Smac/Diablo和Tim 8a，可能会发生独立的Drp 1活性。
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.