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.