Editors' ChoiceCalcium signaling

New connections: Moving through mitosis with the MCU

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Science Signaling  30 Apr 2019:
Vol. 12, Issue 579, eaax8314
DOI: 10.1126/scisignal.aax8314

The MCU ensures that proliferating cells produce the ATP required to progress through the cell cycle.

Cell proliferation is an energetically demanding process. Mitochondrial Ca2+ uptake increases during the cell cycle, an increase that correlates with increased ATP production. Two papers independently describe the role of the mitochondrial Ca2+ uniporter (MCU) during mitosis. In the first paper, Zhao et al. found that in mitotic cells, the MCU mediated mitochondrial Ca2+ transients that coincided with low ATP abundance. Low energy status activates the kinase AMPK, and the authors found that low ATP abundance induced the translocation of AMPK to mitochondria, where it phosphorylated the MCU at Ser57. Mitotic progression required both the mitochondrial Ca2+ transients mediated by the MCU and phosphorylation of the MCU by AMPK. In addition to enhanced mitochondrial Ca2+ uptake, mitochondrial fusion also increases during the cell cycle. In a paper in this issue of Science Signaling, Koval et al. found that the MCU was required to balance Ca2+ concentrations in the cytosol and mitochondria in normal, nontransformed cells. Without the MCU, the excess cytosolic Ca2+ resulted in activation of the kinase CaMKII, which phosphorylated and stimulated the mitochondrial fission factor Drp1. The increase in mitochondrial fission led to reduced ATP output and decreased cellular proliferation, which attenuated responses to the growth factor platelet-derived growth factor (PDGF) in cultured primary cells and suppressed wound healing in mice. Thus, the results of Zhao et al. and Koval et al. demonstrate that the MCU enables ATP production to match energy demands during the cell cycle.

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