The mitochondrial Ca channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation.

The mitochondrial uniporter (MCU) Ca ion channel represents the primary means for Ca uptake into mitochondria. Here we employed and models with MCU genetically eliminated to understand how MCU contributes to tumor formation and progression. Transformation of primary fibroblasts was associated with increased MCU expression, enhanced mitochondrial Ca uptake, suppression of inactivating-phosphorylation of pyruvate dehydrogenase, a modest increase of basal mitochondrial respiration and a significant increase of acute Ca -dependent stimulation of mitochondrial respiration. Inhibition of mitochondrial Ca uptake by genetic deletion of MCU markedly inhibited growth of HEK293T cells and of transformed fibroblasts in mouse xenograft models. Reduced tumor growth was primarily a result of substantially reduced proliferation and fewer mitotic cells , and slower cell proliferation associated with delayed progression through S-phase of the cell cycle. MCU deletion inhibited cancer stem cell-like spheroid formation and cell invasion , both predictors of metastatic potential. Surprisingly, mitochondrial matrix Ca concentration, membrane potential, global dehydrogenase activity, respiration and ROS production were unchanged by genetic deletion of MCU in transformed cells. In contrast, MCU deletion elevated glycolysis and glutaminolysis, strongly sensitized cell proliferation to glucose and glutamine limitation, and altered agonist-induced cytoplasmic Ca signals. Our results reveal a dependence of tumorigenesis on MCU, mediated by a reliance on mitochondrial Ca uptake for cell metabolism and Ca dynamics necessary for cell-cycle progression and cell proliferation.