Mechanism of mitochondrial fission: from the initial formation of fission sites to the membrane scission

线粒体裂变机制：从裂变位点最初形成到膜断裂

• 批准号: 23770231
• 负责人: OTERA Hidenori
• 金额: $ 3万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23770231/
• 关键词: 生体膜; ミトコンドリア; 膜形態; 分裂; ミトコンドリアダイナミクス; アポトーシス; タンパク質選別輸送; ペルオキシソーム

Mitochondrial fission is important for maintaining cellular function, and its dysfunction causes aging, neuronal synaptic loss, and cell death in several human neurologic diseases. The major player of mitochondrial fission is a largely cytosolic member of the dynamin family of GTPases Drp1 in mammals. Endogenous Drp1, observed as dotted structures on mitochondria, was clearly decreased and was dispersed in the cytoplasm in Mff RNAi cells concomitant with mitochondrial network extension. In contrast, Mff overexpression induced mitochondrial fragmentation, concomitant with increased Drp1 recruitment to the mitochondria. These observations indicate that Mff functions as a Drp1 receptor to mediate mitochondrial fission. Drp1 might self-assemble via its ability to homo-oligomerize at Mff-containing foci on the mitochondrial surface, forming spiral structures around the mitochondrial tubules. MiD51/MIEF1 interacts with recombinant Drp1 to inhibit its GTPase activity accompanied by Drp1 oligomerization. In contrast, Mff competes with MiD51/MIEF1 to stimulate Drp1 GTPase activity. Taken together, MiD51/MIEF1 seems to bind oligomerized Drp1 and stabilize them at the surface of the mitochondrial membrane in the GTP-locked state to inhibit mitochondrial fission.

线粒体分裂对维持细胞功能至关重要，其功能障碍导致衰老、神经元突触丧失和一些人类神经系统疾病的细胞死亡。在哺乳动物中，线粒体分裂的主要参与者主要是GTPases Drp1动力蛋白家族的细胞质成员。内源性Drp1在线粒体上呈点状结构，在Mff RNAi细胞中，随着线粒体网络的延伸，Drp1明显减少并分散在细胞质中。相反，Mff过表达诱导线粒体断裂，同时Drp1向线粒体募集增加。这些观察结果表明，Mff作为Drp1受体介导线粒体裂变。Drp1可能通过其在线粒体表面含有mff的聚焦点上的同质寡聚能力进行自组装，在线粒体小管周围形成螺旋结构。MiD51/MIEF1与重组Drp1相互作用抑制其GTPase活性并伴随Drp1寡聚。相反，Mff与MiD51/MIEF1竞争，刺激Drp1 GTPase活性。综上所述，MiD51/MIEF1似乎结合了寡聚的Drp1，并将它们稳定在线粒体膜表面的gtp锁定状态，以抑制线粒体裂变。

项目成果

Regulation and physiologic function of GTPases in mitochondrial fusion and fission in mammals

GTPases 在哺乳动物线粒体融合和裂变中的调节和生理功能

• 发表时间: 2012
• 期刊: Invited Forum Review Article. Antioxid. Redox Signal
• 作者: N. Ishihara;H. Otera;T. Oka;and K;Mihara
• 通讯作者: Mihara

Discovery of membrane receptor for mitochondrial fission GTPase Drp1

线粒体裂变 GTPase Drp1 膜受体的发现

• DOI: 10.4161/sgtp.2.3.16486
• 发表时间: 2011
• 期刊: Small GTPases
• 作者: Otera Hidenori;Mihara Katsuyoshi
• 通讯作者: Mihara Katsuyoshi

ミトコンドリアの分裂を司る分子とその機能

控制线粒体裂变的分子及其功能

• 发表时间: 2011
• 作者: 大寺秀典;三原勝芳
• 通讯作者: 三原勝芳