XPC deficiency is associated with mitochondrial dysfunction, increased mitochondrial H2O2 production and sensitivity to the Complex III inhibitor antimycin A (AA), through a yet unclear mechanism. We found an imbalanced expression of several proteins that participate in important mitochondrial function and increased expression and phosphorylation of the tumor suppressor p53 in Xeroderma pigmentosum complementation group C (XP-C) (XPC-null) cells compared with an isogenic line corrected in locus with wild-type XPC (XPC-wt). Interestingly, inhibition of p53 nuclear import reversed the overexpression of mitochondrial proteins, whereas AA treatment increased p53 expression more strongly in the XP-C cells. However, inhibition of p53 substantially increased XP-C cellular sensitivity to AA treatment, suggesting that p53 is a critical factor mediating the cellular response to mitochondrial stress. On the other hand, treatment with the antioxidant N-acetylcysteine increased glutathione concentration and decreased basal H2O2 production, p53 levels and sensitivity to AA treatment in the XPC-null back to the levels found in XPC-wt cells. Thus, the results suggest a critical role for mitochondrially generated H2O2 in the regulation of p53 expression, which in turn modulates XP-C sensitivity to agents that cause mitochondrial stress.

中文翻译：

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增加的 H2O2 水平和 p53 稳定导致 XPC 缺陷细胞的线粒体功能障碍。

XPC 缺乏与线粒体功能障碍、线粒体 H2O2 产生增加和对复合物 III 抑制剂抗霉素 A (AA) 的敏感性有关，但机制尚不清楚。我们发现与基因座校正的等基因系相比，在色素性干皮病互补组 C (XP-C) (XPC-null) 细胞中，参与重要线粒体功能的几种蛋白质的表达不平衡，并增加了肿瘤抑制因子 p53 的表达和磷酸化。野生型 XPC (XPC-wt)。有趣的是，p53 核输入的抑制逆转了线粒体蛋白的过度表达，而 AA 处理更强烈地增加了 XP-C 细胞中 p53 的表达。然而，p53 的抑制显着增加了 XP-C 细胞对 AA 处理的敏感性，表明 p53 是介导细胞对线粒体应激反应的关键因素。另一方面，用抗氧化剂 N-乙酰半胱氨酸处理增加了谷胱甘肽浓度并降低了基础 H2O2 产生、p53 水平和对 AA 处理的敏感性，回到 XPC-wt 细胞中发现的水平。因此，结果表明线粒体产生的 H2O2 在 p53 表达的调节中起关键作用，p53 表达反过来调节 XP-C 对引起线粒体应激的药物的敏感性。