Structural and functional consequences of c-N-Ras constitutively associated with intact mitochondria
Structural and functional consequences of c-N-Ras constitutively associated with intact mitochondria
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DOI：
10.1016/j.bbamcr.2006.07.015
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发表时间：
2006-10-01
影响因子：
5.1
通讯作者：
Wolfman, Alan
中科院分区：
文献类型：
--
作者：
Wolfman, Janice C.;Planchon, Sarah M.;Wolfman, Alan
我们证明c-N-Ras和c-K（B）-Ras都与纯化的线粒体组成性相关。c-K（B）-Ras与线粒体外膜相关，c-N-Ras与线粒体外膜和线粒体内室相关。c-N-Ras阴性和K-Ras阴性细胞的线粒体形态均异常。通过将N-Ras靶向于线粒体内外区室或通过异位表达c-K（B）-Ras来恢复正常的线粒体形态。线粒体功能受损可导致CHOP和NF κ B活性增加，这是逆行信号传导反应的典型特征。两者在N-Ras阴性细胞中组成性升高，但在K-Ras阴性背景中不升高，并且通过仅靶向线粒体内室的c-N-Ras恢复。令人惊讶的是，发现靶向和功能性降低逆行转录活性的能力都不依赖于c-N-Ras法尼基化。总之，这些数据首次证明了（1）c-N-Ras的法尼基化独立功能和（2）线粒体内室内的N-Ras是线粒体和细胞核之间逆行信号系统的重要组成部分。(c)2006 Elsevier B. V.保留所有权利。
We demonstrate that both c-N-Ras and c-K(B)-Ras are constitutively associated with purified mitochondria. c-K(B)-Ras is associated with the mitochondrial outer membrane, and c-N-Ras is associated with both the outer membrane and inner mitochondrial compartments. The mitochondrial morphology is abnormal in both c-N-Ras negative and K-Ras negative cells. Normal mitochondrial morphology was restored by targeting N-Ras to both the inner and outer mitochondrial compartments, or by ectopically expressing c-K(B)-Ras. Impaired mitochondrial function can result in increased CHOP and NF kappa B activity, typical for a retrograde signaling response. Both are constitutively elevated in the N-Ras negative cells, but not in the K-Ras negative background, and are restored by c-N-Ras targeted exclusively to the inner mitochondrial compartment. Surprisingly, both targeting and the ability to functionally reduce retrograde transcriptional activity were found to be independent of c-N-Ras farnesylation. Overall, these data demonstrate for the first time a (1) farnesylation independent function for c-N-Ras and (2) that N-Ras within the inner mitochondrial compartment is an essential component of the retrograde signaling system between the mitochondria and nucleus. (c) 2006 Elsevier B.V. All rights reserved.