| Cell is the basic unit of living organism with complicated structures.To maintain the normal growth and proliferation,all the cellular processes must be carrying on in order,which needs the accurate regulation of cells on the homeostasis of cellular environment.Especially during some important processes,such as DNA replication,cell division,adjusting cell structure,metabolism and energy state is important for the health and living of cells.As reported,there exist some receptors and controllers of matter and energy inside the cell and they can regulate the cellular activities according to both the inner and outer situations which the cell lies.For example,mTOR can sense the amino acids state inside the cell,and regulate substance metabolism to maintain the steady state of amino acid when amino acid is loss.However,how does the cell coordinate energy metabolism to hold a steady intracellular energy state is remained to be explored.There is a wide consensus that the mitochondria is the energy factory in cells,the ATP generated by oxidative respiration of mitochondria is the main source of energy.Therefore,regulating the strength of the oxidative phophorylation of mitochondria is pivotal to maintain the energy homeostasis of cells.Calcium is a wide-spread second-messenger,it has been reported that calcium can move into mitochondria to regulate the energy-generating state of mitochondria.In our research,we found that the cellular ATP will drop to a low level during mitosis,accompanied by a rapid mitochondrial calcium transient.This can boost mitochondrial oxidative phosphorylation and ATP production to satisfy the need of cells to energy.However,how cells sense the energy defect state in such a process and how to make quick and accurate adaptation remain unclear.We analyzed the sequence of mitochondrial calcium uniporter(MCU)and found that the motif of serine 57 in MCU sequence matches an AMPK consensus phophorylation site.We identified AMPK as the upstream kinase of MCU and proved AMPK can phosphorylate MCU serine 57 in vitro by in vitro kinase experiment and site-mutation experiment.As to calcium experiment,we found phosphorylation of serine 57 can promote the activity of MCU and uptake more calcium into mitochondria to improve the amplitude of oxidative respiration and the production of ATP.By immunofluorescence experiment with a phospho-specific antibody recognizing Ser57-phosphorylated MCU,we found the fluorescence intensity of mitotic cells was higher than that of inter-phase cells,which reminding us that mitotic cells exhibit higher phosphorylated MCU level.This is helpful for cells to keep high-rate mitochondrialoxidative respiration and provide enough energy to mitosis.With deep research,we found MCU serine 57 phosphorylation has no influence on the mitochondrial location of MCU and the oligomerization of MCU,which proved that the main function of phosphorylation is improving the calcium channel activity of MCU.In summary,we found the phosphorylation of MCU by AMPK can facilitate the entry of calcium into mitochondria in mitosis,which boost ATP generation to change the energy defect state.We explained a new approach by which the cells sense the energy state accurately and make adaption quickly by regulating the calcium circumstance.Cell division is the foundation of the growth and proliferation of organisms,so ensuring enough ATP to facilitate the progress of mitosis is pivotal to cells and organisms.In addition,many other cellular processes and extra stimulation such as virus infection and pathogen invasion can probably leave cells an energy defect state.Our research deeply unveiled the mechanism by which cell can sense acute energy defect and make quick adaption to it,this is benefit to the deep insight into energy balance maintenance and self-adaptation. |
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