Mitochondrial Sirt3 supports cell proliferation by regulating glutamine-dependent oxidation in renal cell carcinoma.
Clear cell renal carcinoma (RCC), the most common malignancy arising in the adult kidney, exhibits increased aerobic glycolysis and low mitochondrial respiration due to von Hippel-Lindau gene defects and constitutive hypoxia-inducible factor-α expression. Sirt3 is a major mitochondrial deacetylase that mediates various types of energy metabolism. However, the role of Sirt3 as a tumor suppressor or oncogene in cancer depends on cell types. We show increased Sirt3 expression in the mitochondrial fraction of human RCC tissues. Sirt3 depletion by lentiviral short-hairpin RNA, as well as the stable expression of the inactive mutant of Sirt3, inhibited cell proliferation and tumor growth in xenograft nude mice, respectively. Furthermore, mitochondrial pyruvate, which was used for oxidation in RCC, might be derived from glutamine, but not from glucose and cytosolic pyruvate, due to depletion of mitochondrial pyruvate carrier and the relatively high expression of malic enzyme 2. Depletion of Sirt3 suppressed glutamate dehydrogenase activity, leading to impaired mitochondrial oxygen consumption. Our findings suggest that Sirt3 plays a tumor-progressive role in human RCC by regulating glutamine-derived mitochondrial respiration, particularly in cells where mitochondrial usage of cytosolic pyruvate is severely compromised.
Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Institute of Genetic Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Jieun
J
Choi
Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Institute of Genetic Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Eunjin
E
Koh
Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Institute of Genetic Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Yu Shin
YS
Lee
Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Institute of Genetic Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Hyun-Woo
HW
Lee
Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Institute of Genetic Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Hyeok Gu
HG
Kang
Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Young Eun
YE
Yoon
Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Woong Kyu
WK
Han
Department of Urology, CHA Bundang Medical Center, CHA University, Seongnam 463-712, Republic of Korea.
Kyung Hwa
KH
Choi
Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Institute of Genetic Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea. Electronic address: KYUNGSUP59@yuhs.ac.
Kyung-Sup
KS
Kim
D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction; D056566:Sirtuin 3 / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D024101:Mitochondrial Proteins; D005973:Glutamine; C466093:SIRT3 protein, human; D056566:Sirtuin 3
Glutamate dehydrogenase; Mitochondrial oxidation; Renal cell carcinoma; Sirt3