Department of Biology, University of Padova, Via U. Bassi 58/B, 35131 Padova, Italy.
Int J Mol Sci. 2023 May 4;24(9):8232. doi: 10.3390/ijms24098232.
A coordinated action between nuclear and mitochondrial activities is essential for a proper cellular response to genotoxic stress. Several nuclear transcription factors, including STAT3, translocate to mitochondria to exert mitochondrial function regulation; however, the role of mitochondrial STAT3 (mitoSTAT3) under stressed conditions is still poorly understood. In this study, we examined whether the stable expression of mitoSTAT3 wild-type or mutated at the conserved serine residue (Ser727), which is involved in the mitochondrial function of STAT3, can affect the DNA damage response to UVC radiation. To address this issue, we generated mammalian cells (NIH-3T3 and HCT-116 cells) stably transduced to express the mitochondrial-targeted gene in its wild-type or Ser727 mutated forms. Our results show that cell proliferation is enhanced in mito-transduced cells under both non-stressed and stressed conditions. Once irradiated with UVC, cells expressing wild-type mitoSTAT3 showed the highest cell survival, which was associated with a significant decrease in cell death. Low levels of oxidative stress were detected in UVC-irradiated NIH-3T3 cells expressing mitoSTAT3 wild-type or serine-related dominant active form (Ser727D), confirming a role of mitochondrial STAT3 in minimizing oxidant cellular stress that provides an advantage for cell survival.
核和线粒体活动之间的协调作用对于细胞对遗传毒性应激做出适当的反应是至关重要的。包括 STAT3 在内的几种核转录因子会转位到线粒体，以发挥对线粒体功能的调节作用；然而，在应激条件下线粒体 STAT3（mitoSTAT3）的作用仍知之甚少。在这项研究中，我们研究了稳定表达 mitoSTAT3 野生型或突变型（涉及 STAT3 的线粒体功能的保守丝氨酸残基 Ser727 处突变）是否会影响 UVC 辐射对 DNA 损伤的反应。为了解决这个问题，我们生成了稳定转导表达线粒体靶向基因的哺乳动物细胞（NIH-3T3 和 HCT-116 细胞），其形式为野生型或 Ser727 突变型。我们的结果表明，在非应激和应激条件下，mito 转导的细胞中的细胞增殖增强。用 UVC 照射后，表达野生型 mitoSTAT3 的细胞表现出最高的细胞存活率，这与细胞死亡显著减少有关。在表达 mitoSTAT3 野生型或丝氨酸相关显性激活形式（Ser727D）的 UVC 照射 NIH-3T3 细胞中检测到低水平的氧化应激，这证实了线粒体 STAT3 在最小化氧化应激细胞应激方面的作用，这为细胞存活提供了优势。
