Mitochondrial Sirt3 supports cell proliferation by regulating glutamine-dependent oxidation in renal cell carcinoma

Abstract

Clear cell renal carcinoma (RCC) is the most common malignancy arising in the adult kidney. It exhibits increased aerobic glycolysis and low mitochondrial respiration due to von Hippel-Lindau gene defects and constitutive hypoxia-inducible factor-α expression. Although the “Warburg effect” is considered to be the metabolic hallmark of tumor metabolism, recent studies have elucidated the importance of mitochondrial functions even in cells with minimal mitochondrial biogenesis, such as RCC cells. Sirt3 is a major mitochondrial deacetylase that is involved in the regulation of various types of energy metabolism. The role of Sirt3 as a tumor suppressor or oncogene in human cancer depends on the cell type. Here, we demonstrate that Sirt3 expression was increased 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 pyruvate usage is severely compromised.