Mitochondrial Fission Factor Drp1 Maintains Oocyte Quality via Dynamic Rearrangement of Multiple Organelles
Mitochondrial Fission Factor Drp1 Maintains Oocyte Quality via Dynamic Rearrangement of Multiple Organelles
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DOI：
10.1016/j.cub.2014.08.060
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发表时间：
2014-10-20
期刊：
影响因子：
9.2
通讯作者：
Ishihara, Naotada
中科院分区：
文献类型：
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作者：
Udagawa, Osamu;Ishihara, Takaya;Ishihara, Naotada
线粒体是动态细胞器，其通过响应细胞信号传导和分化而主动融合和分裂来改变其形态[1，2]。线粒体分裂在哺乳动物体内的作用已经通过使用线粒体分裂调节GTd 1 Drp 1的组织特异性敲除（KO）小鼠[3，4]以及分析携带Drp 1点突变的人类患者[5]来检查，表明Drp 1对于胚胎和新生儿发育以及神经元功能是必需的。在卵母细胞成熟和衰老过程中，线粒体和内质网（ER）等各种膜细胞器的结构发生动态变化[6，7]，其细胞器聚集与生殖细胞的形成和表观遗传调节有关[8-10]。然而，在卵母细胞的发育和老化过程中的细胞器动力学的分子机制还没有得到很好的理解。在这里，我们分析了卵母细胞特异性线粒体分裂因子Drp 1缺陷小鼠，发现线粒体分裂是卵泡成熟和排卵的年龄依赖性方式所必需的。在KO卵母细胞中，线粒体与其他细胞器如ER和分泌囊泡高度聚集，这导致Ca 2+信号传导受损，通过分泌进行细胞间通讯，以及减数分裂恢复。我们进一步发现，从老年小鼠卵母细胞显示减少Drp 1依赖的线粒体分裂和有缺陷的细胞器形态发生，类似于Drp 1 KO卵母细胞。基于这些发现，线粒体分裂似乎通过多细胞器重排维持卵母细胞的能力。
Mitochondria are dynamic organelles that change their morphology by active fusion and fission in response to cellular signaling and differentiation [1, 2]. The in vivo role of mitochondrial fission in mammals has been examined by using tissue-specific knockout (KO) mice of the mitochondria fission-regulating GTPase Drp1 [3, 4], as well as analyzing a human patient harboring a point mutation in Drpl [5], showing that Drp1 is essential for embryonic and neonatal development and neuronal function. During oocyte maturation and aging, structures of various membrane organelles including mitochondria and the endoplasmic reticulum (ER) are changed dynamically [6, 7], and their organelle aggregation is related to germ cell formation and epigenetic regulation [8-10]. However, the underlying molecular mechanisms of organelle dynamics during the development and aging of oocytes have not been well understood. Here, we analyzed oocyte-specific mitochondrial fission factor Drp1-deficient mice and found that mitochondrial fission is essential for follicular maturation and ovulation in an age-dependent manner. Mitochondria were highly aggregated with other organelles, such as the ER and secretory vesicles, in KO oocyte, which resulted in impaired Ca2+ signaling, intercellular communication via secretion, and meiotic resumption. We further found that oocytes from aged mice displayed reduced Drp1-dependent mitochondrial fission and defective organelle morphogenesis, similar to Drp1 KO oocytes. On the basis of these findings, it appears that mitochondrial fission maintains the competency of oocytes via multiorganelle rearrangement.