AMPK-mediated activation of MCU stimulates mitochondrial Ca entry to promote mitotic progression.

The capacity of cells to alter bioenergetics in response to the demands of various biological processes is essential for normal physiology. The coordination of energy sensing and production with highly energy-demanding cellular processes, such as cell division, is poorly understood. Here, we show that a cell cycle-dependent mitochondrial Ca transient connects energy sensing to mitochondrial activity for mitotic progression. The mitochondrial Ca uniporter (MCU) mediates a rapid mitochondrial Ca transient during mitosis. Inhibition of mitochondrial Ca transients via MCU depletion causes spindle checkpoint-dependent mitotic delay. Cellular ATP levels drop during early mitosis, and the mitochondrial Ca transients boost mitochondrial respiration to restore energy homeostasis. This is achieved through mitosis-specific MCU phosphorylation and activation by the mitochondrial translocation of energy sensor AMP-activated protein kinase (AMPK). Our results establish a critical role for AMPK- and MCU-dependent mitochondrial Ca signalling in mitosis and reveal a mechanism of mitochondrial metabolic adaptation to acute cellular energy stress.