Identification of a novel protein MICS1 that is involved in maintenance of mitochondrial morphology and apoptotic release of cytochrome c
Identification of a novel protein MICS1 that is involved in maintenance of mitochondrial morphology and apoptotic release of cytochrome c
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DOI：
10.1091/mbc.e07-12-1205
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发表时间：
2008-06-01
影响因子：
3.3
通讯作者：
Mihara, Katsuyoshi
中科院分区：
文献类型：
--
作者：
Oka, Toshihiko;Sayano, Tomoko;Mihara, Katsuyoshi
线粒体形态在膜融合和分裂的平衡中动态变化，以响应环境、细胞周期和凋亡刺激。在这里，我们报道了一种新的线粒体蛋白MICS1，它参与了特定嵴结构的线粒体形态和线粒体细胞色素c的凋亡释放。MICS1是一种具有可切割前序和多个跨膜片段的细胞膜蛋白，属于Bi-1超家族。MICS1下调导致线粒体断裂和嵴解体，刺激促凋亡蛋白的释放。抗凋亡蛋白Bcl-XL的表达并不能阻止MICS1下调引起的线粒体形态改变，说明MICS1在维持线粒体形态方面的作用与凋亡通路中的功能是分离的。无论是否发生Bax靶向，MICS1的过量产生诱导线粒体聚集并部分抑制细胞凋亡过程中细胞色素c的释放。MICS1与细胞色素c交联而不破坏膜的完整性。因此，MICS1促进细胞色素c与内膜紧密结合。此外，在低血清条件下，细胞色素c的凋亡延迟释放与MICS1上调相关，但线粒体形态没有明显变化，表明MICS1单独参与线粒体形态和细胞色素c释放。
Mitochondrial morphology dynamically changes in a balance of membrane fusion and fission in response to the environment, cell cycle, and apoptotic stimuli. Here, we report that a novel mitochondrial protein, MICS1, is involved in mitochondrial morphology in specific cristae structures and the apoptotic release of cytochrome c from the mitochondria. MICS1 is an inner membrane protein with a cleavable presequence and multiple transmembrane segments and belongs to the Bi-1 super family. MICS1 down-regulation causes mitochondrial fragmentation and cristae disorganization and stimulates the release of proapoptotic proteins. Expression of the anti-apoptotic protein Bcl-XL does not prevent morphological changes of mitochondria caused by MICS1 down-regulation, indicating that MICS1 plays a role in maintaining mitochondrial morphology separately from the function in apoptotic pathways. MICS1 overproduction induces mitochondrial aggregation and partially inhibits cytochrome c release during apoptosis, regardless of the occurrence of Bax targeting. MICS1 is cross-linked to cytochrome c without disrupting membrane integrity. Thus, MICS1 facilitates the tight association of cytochrome c with the inner membrane. Furthermore, under low-serum condition, the delay in apoptotic release of cytochrome c correlates with MICS1 up-regulation without significant changes in mitochondrial morphology, suggesting that MICS1 individually functions in mitochondrial morphology and cytochrome c release.