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SIRT3 Overexpression Inhibits Growth of Kidney Tumor Cells and Enhances Mitochondrial Biogenesis
- Source :
- Journal of proteome research. 17(9)
- Publication Year :
- 2018
-
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.
- Subjects :
- 0301 basic medicine
Proteomics
Mitochondrial DNA
SIRT3
medicine.disease_cause
Kidney
Biochemistry
DNA, Mitochondrial
Mitochondrial Proteins
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
Sirtuin 3
medicine
Humans
Metabolomics
Cell Proliferation
Organelle Biogenesis
Cell growth
Chemistry
Acetylation
Epithelial Cells
General Chemistry
TFAM
Warburg effect
Cell biology
Mitochondria
DNA-Binding Proteins
Gene Expression Regulation, Neoplastic
Oxidative Stress
030104 developmental biology
Proteostasis
HEK293 Cells
Mitochondrial biogenesis
030220 oncology & carcinogenesis
Carcinogenesis
Reactive Oxygen Species
Protein Processing, Post-Translational
Transcription Factors
Subjects
Details
- ISSN :
- 15353907
- Volume :
- 17
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Journal of proteome research
- Accession number :
- edsair.doi.dedup.....e71e868228cc758c6cd14e0482646a6e