J Proteome Res. 2018 Sep 7;17(9):3143-3152. doi: 10.1021/acs.jproteome.8b00260. Epub 2018 Aug 21.

SIRT3 Overexpression Inhibits Growth of Kidney Tumor Cells and Enhances Mitochondrial Biogenesis.

Liu H1, Li S2, Liu X1, Chen Y1,3, Deng H1.

Author information

1MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences , Tsinghua University , Beijing 100084 , China.2University of California, Davis , Davis , California 95616 , United States.3Tsinghua University-Peking University Joint Center for Life Sciences , Beijing 100084 , China.

Abstract

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.

KEYWORDS:

SIRT3; TFAM; clear cell renal cell carcinoma; deacetylation; mitochondrial biogenesis; proteomics

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