Mitochondrial Ca2+ and cell cycle regulation

It has been demonstrated for more than 40 years that intracellular calcium (Ca2+) controls a variety of cellular functions, including mitochondrial metabolism and cell proliferation. Cytosolic Ca2+ fluctuation during key stages of the cell cycle can lead to mitochondrial Ca2+ uptake and subsequent activation of mitochondrial oxidative phosphorylation and a range of signaling. However, the relationship between mitochondrial Ca2+ and cell cycle progression has long been neglected because the molecule responsible for Ca2+ uptake has been unknown. Recently, the identification of the mitochondrial Ca2+ uniporter (MCU) has led to key advances. With improved Ca2+ imaging and detection, effects of MCU-mediated mitochondrial Ca2+ have been observed at different stages of the cell cycle. Elevated Ca2+ signaling boosts ATP and ROS production, remodels cytosolic Ca2+ pathways and reprograms cell fate-determining networks. These findings suggest that manipulating mitochondrial Ca2+ signaling may serve as a potential strategy in the control of many crucial biological events, such as tumor development and cell division in hematopoietic stem cells (HSCs). In this review, we summarize the current understanding of the role of mitochondrial Ca2+ signaling during different stages of the cell cycle and highlight the potential physiological and pathological significance of mitochondrial Ca2+ signaling.