SIRT3 is a NAD⁺-dependent mitochondrial protein deacetylase implicated in the regulation of central metabolism and mitochondrial proteostasis. SIRT3 is downregulated in clear cell renal cell carcinoma (ccRCC), which is the most common form of renal cancer. Although ccRCC is characterized by a typical Warburg-like phenotype, mitochondrial dysfunction and elevated fat deposition, it is unknown whether SIRT3 plays a role in tumorigenesis and the development of this disease. In the present study, we found that SIRT3 overexpression and knockdown had opposing effects on the growth of ccRCC cells, decreasing and increasing the rate of cell proliferation, respectively. SIRT3 overexpression also increased mitochondrial mass in ccRCC cells. Unexpectedly, SIRT3 overexpression increased ROS levels, and sensitized cells to oxidative stress. Metabolomics and quantitative proteomics showed that SIRT3 overexpression alterd cellular metabolism and reversed the Warburg effect in ccRCC cells. Further studies demonstrated that SIRT3 promoted mitochondrial biogenesis by increasing both the expression and deacetylation of TFAM (transcription factor A, mitochondrial). Mutagenesis experiments revealed that acetylation of TFAM at K154 impaired TFAM interaction with mitochondrial DNA, thereby decreasing the activity of the protein and, consequently, mitochondrial biogenesis. Overall, our results suggest that SIRT3 regulates mitochondrial biogenesis and that its downregulation promotes a Warburg phenotype in ccRCC.

中文翻译：

---

SIRT3过表达抑制肾脏肿瘤细胞的生长并增强线粒体的生物发生。

SIRT3是NAD ⁺依赖性线粒体蛋白脱乙酰基酶，参与中央代谢和线粒体蛋白稳态的调节。SIRT3在透明细胞肾细胞癌（ccRCC）中被下调，后者是肾癌的最常见形式。尽管ccRCC具有典型的Warburg样表型，线粒体功能障碍和脂肪沉积增加的特征，但尚不清楚SIRT3是否在该疾病的发生和发展中起作用。在本研究中，我们发现SIRT3的过表达和敲低对ccRCC细胞的生长有相反的影响，分别降低和增加细胞的增殖速率。SIRT3过表达还增加了ccRCC细胞中的线粒体质量。不料，SIRT3过表达增加了ROS水平，并使细胞对氧化应激敏感。代谢组学和定量蛋白质组学表明，SIRT3的过表达改变了细胞代谢，并逆转了ccRCC细胞中的Warburg效应。进一步的研究表明，SIRT3通过增加TFAM（转录因子A，线粒体）的表达和去乙酰化来促进线粒体的生物发生。诱变实验表明，TFAM在K154处的乙酰化会破坏TFAM与线粒体DNA的相互作用，从而降低蛋白质的活性，从而降低线粒体的生物发生。总体而言，我们的结果表明SIRT3调节线粒体的生物发生，并且其下调促进了ccRCC中的Warburg表型。