Loss of Drp1 function alters OPA1 processing and changes mitochondrial membrane organization
Loss of Drp1 function alters OPA1 processing and changes mitochondrial membrane organization
复制标题
DOI：
10.1016/j.yexcr.2009.04.016
复制
发表时间：
2009-08-01
影响因子：
3.7
通讯作者：
Santel, Ansgar
中科院分区：
文献类型：
--
作者：
Moepert, Kristin;Hajek, Petr;Santel, Ansgar
RNAi 介导的 Drp1 功能丧失通过将线粒体裂变和融合的平衡转向无对抗融合来改变培养的 HeLa 和 HUVEC 细胞中的线粒体形态。随着时间的推移，Drp1 表达的抑制会导致高度分支的线粒体网络以及“凸起”状结构的形成。线粒体形态的这些变化伴随着线粒体融合蛋白 1 (Mfn1) 和 2 (Mfn2) 水平的降低以及 OPA1 亚型的蛋白水解加工的改变，从而抑制细胞增殖。此外，我们的数据表明，凸起的形成是由 Mfn1 作用以及特定的蛋白水解短 OPA1 (s-OPA1) 变体驱动的：在缺乏 Drp1 的情况下，Mfn2 的丢失会导致 Mfn1 水平以及加工的 s-OPA1 同种型的增加，从而增强连续的“融合”和凸起的形成。此外，凸起的形成可能反映了 s-OPA1 线粒体膜重塑活性，导致细胞色素 c 沉积物的区室化。 Yme1L 和 PHB2 蛋白似乎与观察到的 Drp1 RNAi 后 OPA1 蛋白水解增强无关，表明存在其他 OPA1 加工控制蛋白。总而言之，Drp1 似乎通过使线粒体融合蛋白和 OPA1 的蛋白质水平失衡来影响线粒体融合机制的活性。 (C) 2009 Elsevier Inc. 保留所有权利。
RNAi mediated loss of Drp1 function changes mitochondrial morphology in cultured HeLa and HUVEC cells by shifting the balance of mitochondrial fission and fusion towards unopposed fusion. Over time, inhibition of Drp1 expression results in the formation of a highly branched mitochondrial network along with "bulge"-like structures. These changes in mitochondrial morphology are accompanied by a reduction in levels of Mitofusin 1 (Mfn1) and 2 (Mfn2) and a modified proteolytic processing of OPA1 isoforms, resulting in the inhibition of cell proliferation. In addition, our data imply that bulge formation is driven by Mfn1 action along with particular proteolytic short-OPA1 (s-OPA1) variants: Loss of Mfn2 in the absence of Drp1 results in an increase of Mfn1 levels along with processed s-OPA1-isoforms, thereby enhancing continuous "fusion" and bulge formation. Moreover, bulge formation might reflect s-OPA1 mitochondrial membrane remodeling activity, resulting in the compartmentalization of cytochrome c deposits. The proteins Yme1L and PHB2 appeared not associated with the observed enhanced OPA1 proteolysis upon RNAi of Drp1, suggesting the existence of other OPA1 processing controlling proteins. Taken together, Drp1 appears to affect the activity of the mitochondrial fusion machinery by unbalancing the protein levels of mitofusins and OPA1. (C) 2009 Elsevier Inc. All rights reserved.