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SirT3 Regulates the Mitochondrial Unfolded Protein Response

机译：SirT3调节线粒体展开的蛋白质反应。

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The mitochondria of cancer cells are characterized by elevated oxidative stress caused by reactive oxygen species (ROS). Such an elevation in ROS levels contributes to mitochondrial reprogramming and malignant transformation. However, high levels of ROS can cause irreversible damage to proteins, leading to their misfolding, mitochondrial stress, and ultimately cell death. Therefore, mechanisms to overcome mitochondrial stress are needed. The unfolded protein response (UPR) triggered by accumulation of misfolded proteins in the mitochondria (UPRmt) has been reported recently. So far, the UPRmt has been reported to involve the activation of CHOP and estrogen receptor alpha (ERα). The current study describes a novel role of the mitochondrial deacetylase SirT3 in the UPRmt. Our data reveal that SirT3 acts to orchestrate two pathways, the antioxidant machinery and mitophagy. Inhibition of SirT3 in cells undergoing proteotoxic stress severely impairs the mitochondrial network and results in cellular death. These observations suggest that SirT3 acts to sort moderately stressed from irreversibly damaged organelles. Since SirT3 is reported to act as a tumor suppressor during transformation, our findings reveal a dual role of SirT3. This novel role of SirT3 in established tumors represents an essential mechanism of adaptation of cancer cells to proteotoxic and mitochondrial stress.
机译：癌细胞的线粒体的特征在于由活性氧（ROS）引起的氧化应激升高。 ROS水平的这种升高有助于线粒体重编程和恶性转化。但是，高水平的ROS可能对蛋白质造成不可逆转的破坏，从而导致蛋白质错误折叠，线粒体应激，并最终导致细胞死亡。因此，需要克服线粒体应激的机制。最近已经报道了由错误折叠的蛋白质在线粒体（UPR mt ）中积累触发的未折叠蛋白质反应（UPR）。到目前为止，据报道UPR mt 涉及CHOP和雌激素受体α（ERα）的激活。目前的研究描述了线粒体脱乙酰基酶SirT3在UPR mt 中的新作用。我们的数据表明，SirT3起到协调两个途径的作用，即抗氧化剂机制和线粒体作用。在经历蛋白毒性应激的细胞中抑制SirT3会严重损害线粒体网络并导致细胞死亡。这些观察结果表明，SirT3的作用是对不可逆损伤的细胞器施加适度的压力。由于据报道SirT3在转化过程中起着抑癌作用，因此我们的发现揭示了SirT3的双重作用。 SirT3在已建立的肿瘤中的这种新作用代表了癌细胞适应蛋白毒性和线粒体应激的基本机制。

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