Autophagy is a highly regulated evolutionarily conserved metabolic process induced by stress and energy deprivation. Here, we show that DNA polymerase gamma (Polγ) deficiency activates a selective prosurvival autophagic response via mitochondria-mediated reactive oxygen species (ROS) signaling and the mammalian target of rapamycin complex 2 (mTORC2) activities. In keratinocytes, Polγ deficiency causes metabolic adaptation that triggers cytosolic sensing of energy demand for survival. Knockdown of Polγ causes mitochondrial stress, decreases mitochondrial energy production, increases glycolysis, increases the expression of autophagy-associated genes, and enhances AKT phosphorylation and cell proliferation. Deficiency of Polγ preferentially activates mTORC2 formation to increase autophagy and cell proliferation, and knocking down Rictor abrogates these responses. Overexpression of Rictor, but not Raptor, reactivates autophagy in Polγ-deficient cells. Importantly, inhibition of ROS by a mitochondria-selective ROS scavenger abolishes autophagy and cell proliferation. These results identify Rictor as a critical link between mitochondrial stress, ROS, and autophagy. They represent a major shift in our understanding of the prosurvival role of the mTOR complexes and highlight mitochondria-mediated ROS as a prosurvival autophagy regulator during cancer development.

中文翻译：

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DNA聚合酶γ（Polγ）缺乏会通过线粒体介导的ROS信号触发选择性mTORC2生存自噬反应。

自噬是由压力和能量剥夺引起的高度调控的进化保守的代谢过程。在这里，我们表明DNA聚合酶伽玛（Polγ）缺乏激活通过线粒体介导的活性氧（ROS）信号传导和雷帕霉素复合物2（mTORC2）活动的哺乳动物目标选择性的生存前自噬反应。在角质形成细胞中，Polγ缺乏会引起代谢适应，从而触发细胞质感测生存所需能量。抑制Polγ会引起线粒体应激，降低线粒体能量产生，增加糖酵解，增加自噬相关基因的表达，并增强AKT磷酸化和细胞增殖。Polγ的缺乏会优先激活mTORC2的形成，从而增加自噬和细胞增殖，并取消Rictor将取消这些响应。Rictor（而非Raptor）的过表达会激活Polγ缺陷细胞中的自噬。重要的是，线粒体选择性ROS清除剂对ROS的抑制作用消除了自噬和细胞增殖。这些结果表明，Rictor是线粒体应激，ROS和自噬之间的关键环节。它们代表了我们对mTOR复合物的生存作用的理解的重大转变，并突出了线粒体介导的ROS在癌症发展过程中作为生存自噬调节剂。和自噬。它们代表了我们对mTOR复合物的生存作用的理解的重大转变，并突出了线粒体介导的ROS在癌症发展过程中作为生存自噬调节剂。和自噬。它们代表了我们对mTOR复合物的生存作用的理解的重大转变，并突出了线粒体介导的ROS在癌症发展过程中作为生存自噬调节剂。