Sirt3-mediated mitophagy protects tumor cells against apoptosis under hypoxia.
Sirt3-mediated mitophagy protects tumor cells against apoptosis under hypoxia.
复制标题
Sirt3介导的线粒体自噬保护肿瘤细胞在缺氧下免于凋亡
DOI：
10.18632/oncotarget.9717
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发表时间：
2016-07-12
期刊：
影响因子：
--
通讯作者：
Cheng Y
中科院分区：
文献类型：
--
作者：
Qiao A;Wang K;Yuan Y;Guan Y;Ren X;Li L;Chen X;Li F;Chen AF;Zhou J;Yang JM;Cheng Y
Sirt 3是一种线粒体脱乙酰酶，通过影响蛋白质乙酰化参与多种细胞过程的调控。本研究的目的是探讨Sirt 3在线粒体自噬（mitophagy）中的作用，线粒体自噬是一种特异性自噬清除受损线粒体的过程。我们发现，通过RNA干扰沉默Sirt 3在人脑胶质瘤细胞中的表达减弱了缺氧诱导的LC 3在线粒体上的定位和线粒体的降解。这些结果表明，这种蛋白质脱乙酰酶在缺氧条件下诱导癌细胞线粒体自噬的重要参与。此外，我们证明了Sirt 3通过增加VDAC 1与Parkin的相互作用来激活缺氧诱导的线粒体自噬。在经历缺氧的细胞中，抑制Sirt 3介导的线粒体自噬进一步降低了线粒体膜电位，并增加了ROS的积累，从而通过蛋白酶体途径触发抗凋亡蛋白Mcl-1和生存素的降解。Sirt 3表达的沉默也促进了细胞凋亡，并增强了癌细胞对缺氧的敏感性。在人乳腺癌细胞中也观察到Sirt 3在自噬和凋亡中的调节作用。目前的研究结果表明，Sirt 3作为一种新的调节剂耦合线粒体自噬和细胞凋亡，两个重要的细胞过程，决定细胞的生存和死亡。
Sirt3, a mitochondrial deacetylase, participates in the regulation of multiple cellular processes through its effect on protein acetylation. The objective of this study was to explore the role of Sirt3 in the mitochondrial autophagy (mitophagy), a process of the specific autophagic elimination of damaged mitochondria. We found that silencing of Sirt3 expression in human glioma cells by RNA interference blunted the hypoxia-induced the localization of LC3 on the mitochondria, and the degradation of mitochondria. These results suggest an important involvement of this protein deacetylase in the induction of mitophagy in cancer cells subjected to hypoxia. Further, we demonstrated that Sirt3 activated the hypoxia-induced mitophagy by increasing the interaction of VDAC1 with Parkin. In the cells subjected to hypoxia, inhibition of Sirt3-mediated mitophagy further decreased the mitochondrial membrane potential, and increased the accumulation of ROS that triggers the degradation of anti-apoptotic proteins Mcl-1 and survivin through the proteasomal pathway. Silencing of Sirt3 expression also promoted apoptosis, and enhanced the sensitivity of cancer cells to hypoxia. The regulatory role of Sirt3 in autophagy and apoptosis was also observed in human breast cancer cells. The results of the current study reveal Sirt3 as a novel regulator coupling mitophagy and apoptosis, two important cellular processes that determine cellular survival and death.
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DOI：
10.1073/pnas.0913485107
发表时间：
2010-03-16
影响因子：
11.1
作者：
Ziviani, Elena;Tao, Ran N.;Whitworth, Alexander J.
通讯作者：
Whitworth, Alexander J.
影响因子：
29
作者：
Qiu, Xiaolei;Brown, Katharine;Chen, Danica
通讯作者：
Chen, Danica
影响因子：
5.2
作者：
Lee, Sung-Jun;Noh, Hyo-Jeong;Lee, Tae-Jin
通讯作者：
Lee, Tae-Jin
影响因子：
12.4
作者：
Pellegrini, L.;Pucci, B.;Tafani, M.
通讯作者：
Tafani, M.
影响因子：
4
作者：
Shulga, Nataly;Pastorino, John G.
通讯作者：
Pastorino, John G.