Drp1-dependent mitochondrial fission via MiD49/51 is essential for apoptotic cristae remodeling.
Drp1-dependent mitochondrial fission via MiD49/51 is essential for apoptotic cristae remodeling.
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DOI：
10.1083/jcb.201508099
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发表时间：
2016-02-29
期刊：
影响因子：
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通讯作者：
Mihara K
中科院分区：
文献类型：
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作者：
Otera H;Miyata N;Kuge O;Mihara K
Drp 1依赖的线粒体分裂通过MiD 49和MiD 51，但不是通过Mff，是必不可少的嵴重塑，以促进细胞色素c的释放在早期阶段的内在凋亡。线粒体分裂促进细胞色素c在内源性细胞凋亡过程中从嵴内空间释放到细胞质中，尽管线粒体分裂因子Drp 1及其线粒体受体Mff、MiD 49和MiD 51如何参与该反应仍然是难以捉摸的。在这里，我们分析了这些受体与它们的敲除（KO）细胞系的功能划分。与Mff-KO细胞形成鲜明对比的是，MiD 49/MiD 51-KO和Drp 1-KO细胞在凋亡期间完全抵抗嵴重塑和细胞色素c释放。MiD 49/51-KO细胞中的这种表型，而不是Drp 1-KO细胞中的这种表型，通过破坏嵴结构的处理如OPA 1耗竭而完全消除。出乎意料的是，通常认为通过稳定嵴结构来抵抗细胞色素c释放的OPA 1寡聚体在Drp 1-KO和MiD 49/51-KO细胞中类似地分解，表明OPA 1寡聚体的分解与细胞色素c释放的嵴重塑没有直接联系。总之，这些结果表明，Drp 1依赖性线粒体分裂通过MiD 49/MiD 51调节内在凋亡过程中的嵴重塑。
Drp1-dependent mitochondrial fission through MiD49 and MiD51, but not through Mff, is essential for cristae remodeling to facilitate cytochrome c release during the early phase of intrinsic apoptosis. Mitochondrial fission facilitates cytochrome c release from the intracristae space into the cytoplasm during intrinsic apoptosis, although how the mitochondrial fission factor Drp1 and its mitochondrial receptors Mff, MiD49, and MiD51 are involved in this reaction remains elusive. Here, we analyzed the functional division of these receptors with their knockout (KO) cell lines. In marked contrast to Mff-KO cells, MiD49/MiD51-KO and Drp1-KO cells completely resisted cristae remodeling and cytochrome c release during apoptosis. This phenotype in MiD49/51-KO cells, but not Drp1-KO cells, was completely abolished by treatments disrupting cristae structure such as OPA1 depletion. Unexpectedly, OPA1 oligomers generally thought to resist cytochrome c release by stabilizing the cristae structure were similarly disassembled in Drp1-KO and MiD49/51-KO cells, indicating that disassembly of OPA1 oligomers is not directly linked to cristae remodeling for cytochrome c release. Together, these results indicate that Drp1-dependent mitochondrial fission through MiD49/MiD51 regulates cristae remodeling during intrinsic apoptosis.