State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, National Center of Biomedical Analysis, Beijing, China.
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
Nat Cell Biol. 2019 Apr;21(4):476-486. doi: 10.1038/s41556-019-0296-3. Epub 2019 Mar 11.
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.
细胞改变生物能量以响应各种生物过程的需求的能力对于正常生理至关重要。能量感应和产生与高度耗能的细胞过程（如细胞分裂）的协调尚不清楚。在这里，我们表明，细胞周期依赖性线粒体 Ca 瞬变将能量感应与有丝分裂进展的线粒体活性联系起来。线粒体 Ca 单向转运体（MCU）在有丝分裂过程中介导快速的线粒体 Ca 瞬变。通过 MCU 耗竭抑制线粒体 Ca 瞬变会导致纺锤体检查点依赖性有丝分裂延迟。细胞内 ATP 水平在早期有丝分裂期间下降，而线粒体 Ca 瞬变通过增加线粒体呼吸来恢复能量稳态。这是通过有丝分裂特异性 MCU 磷酸化和由能量传感器 AMP 激活蛋白激酶（AMPK）的线粒体易位来实现的。我们的研究结果确立了 AMPK 和 MCU 依赖性线粒体 Ca 信号在有丝分裂中的关键作用，并揭示了线粒体代谢适应急性细胞能量应激的机制。
