Novel roles of RTN4 and CLIMP-63 in regulating mitochondrial structure, bioenergetics and apoptosis.
Novel roles of RTN4 and CLIMP-63 in regulating mitochondrial structure, bioenergetics and apoptosis.
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DOI：
10.1038/s41419-022-04869-8
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发表时间：
2022-05-04
影响因子：
9
通讯作者：
Varadarajan, Shankar
中科院分区：
文献类型：
--
作者：
Carter, Rachel J.;Milani, Mateus;Beckett, Alison J.;Liu, Shiyu;Prior, Ian A.;Cohen, Gerald M.;Varadarajan, Shankar
线粒体周围包裹着内质网(ER)膜，促进了Drp1在分裂前向线粒体膜的募集。为了研究线粒体结构和功能背景下ER膜和Drp1之间的复杂相互作用，我们下调了两个关键的ER形成蛋白RTN4和CLIP-63的表达，并证明了显著的线粒体过度融合和ER-线粒体接触减少，尽管它们对ER结构的调节存在差异。尽管在缺乏RTN4或CLIMP-63的细胞中，线粒体对Drp1的募集没有改变，但线粒体功能的几个方面，如mtDNA编码的翻译、呼吸能力和细胞凋亡，都受到了显著的阻碍。进一步的机制研究表明，CRAMP-63在眉骨重塑(OPA1蛋白分解)和Drp1介导的线粒体分裂中是必需的，而RTN4和CLIMP-63都调节Bax的募集到内质网和线粒体膜上，从而使细胞色素c释放和细胞凋亡，从而在线粒体结构和功能的调节中发挥新的和独特的作用。
The recruitment of DRP1 to mitochondrial membranes prior to fission is facilitated by the wrapping of endoplasmic reticulum (ER) membranes around the mitochondria. To investigate the complex interplay between the ER membranes and DRP1 in the context of mitochondrial structure and function, we downregulate two key ER shaping proteins, RTN4 and CLIMP-63, and demonstrate pronounced mitochondrial hyperfusion and reduced ER-mitochondria contacts, despite their differential regulation of ER architecture. Although mitochondrial recruitment of DRP1 is unaltered in cells lacking RTN4 or CLIMP-63, several aspects of mitochondrial function, such as mtDNA-encoded translation, respiratory capacity and apoptosis are significantly hampered. Further mechanistic studies reveal that CLIMP-63 is required for cristae remodeling (OPA1 proteolysis) and DRP1-mediated mitochondrial fission, whereas both RTN4 and CLIMP-63 regulate the recruitment of BAX to ER and mitochondrial membranes to enable cytochrome c release and apoptosis, thereby performing novel and distinct roles in the regulation of mitochondrial structure and function.
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