Research ArticleCalcium signaling

Loss of MCU prevents mitochondrial fusion in G1-S phase and blocks cell cycle progression and proliferation

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Science Signaling  30 Apr 2019:
Vol. 12, Issue 579, eaav1439
DOI: 10.1126/scisignal.aav1439

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Balancing Ca2+ pools in proliferating cells

Cell proliferation is an energetically demanding process. During the cell cycle, mitochondrial fusion and mitochondrial Ca2+ uptake increase, both of which correlate with increased ATP production. Koval et al. found that the mitochondrial Ca2+ uniporter (MCU) was required to balance Ca2+ concentrations in the cytosol and mitochondria. Without the MCU, the excess cytosolic Ca2+ resulted in mitochondrial fission mediated by Drp1, reduced ATP output, and decreased cellular proliferation. Thus, the MCU enables ATP production to match energy demands during the cell cycle.

Abstract

The role of the mitochondrial Ca2+ uniporter (MCU) in physiologic cell proliferation remains to be defined. Here, we demonstrated that the MCU was required to match mitochondrial function to metabolic demands during the cell cycle. During the G1-S transition (the cycle phase with the highest mitochondrial ATP output), mitochondrial fusion, oxygen consumption, and Ca2+ uptake increased in wild-type cells but not in cells lacking MCU. In proliferating wild-type control cells, the addition of the growth factors promoted the activation of the Ca2+/calmodulin-dependent kinase II (CaMKII) and the phosphorylation of the mitochondrial fission factor Drp1 at Ser616. The lack of the MCU was associated with baseline activation of CaMKII, mitochondrial fragmentation due to increased Drp1 phosphorylation, and impaired mitochondrial respiration and glycolysis. The mitochondrial fission/fusion ratio and proliferation in MCU-deficient cells recovered after MCU restoration or inhibition of mitochondrial fragmentation or of CaMKII in the cytosol. Our data highlight a key function for the MCU in mitochondrial adaptation to the metabolic demands during cell cycle progression. Cytosolic CaMKII and the MCU participate in a regulatory circuit, whereby mitochondrial Ca2+ uptake affects cell proliferation through Drp1.

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